Spray ejector device and methods of use

ABSTRACT

An ejector device for ejecting droplets of fluid onto a surface includes an ejector mechanism attached to a fluid reservoir through a fluid loading plate that is configured to pierce the reservoir and channel the fluid to a rear surface of the ejector mechanism by capillary action. The ejector mechanism may have a centro-symmetric configuration with a lead free piezo actuator and may be covered by an auto-closing cover.

RELATED APPLICATIONS

The present application claims the benefit of the filing date of USProvisional Application Nos. 61/636,559 filed Apr. 20, 2012; 61/636,565filed Apr. 20, 2012; 61/643,150 filed May 4, 2012; 61/722,611 filed Nov.5, 2012, and 61/722,616 filed Nov. 5, 2012, the contents of which areherein incorporated by reference in their entireties.

FIELD OF THE DISCLOSURE

The present disclosure relates to ejector devices, and methods ofmanufacturing ejector devices. In particular, it relates to devices andmethods for ejecting mists, or sprays of micro-droplets.

BACKGROUND OF THE INVENTION

Using spray devices to administer products in the form of mists orsprays is an area with large potential for safe, easy-to-use products. Amajor challenge in providing such a device is to provide consistent andaccurate delivery of suitable doses and to avoid contamination of theproduct being delivered.

An important area where spray devices are needed is in delivery of eyemedications. The application of fluids, as in the case of eye drops, hasalways posed a problem, especially for children and animals, which tendto blink or jerk at the critical moment of administration, causing thedroplet to land on the eyelid, nose or other part of the face. Theimpact of a large drop or drops of fluid on the eyeball, especially whenthe fluid is at a different temperature, also tends to produce ablinking reaction. The elderly also often lose the hand coordinationnecessary to get the eye drops into their eyes. Stroke victims havesimilar difficulties. Currently, many of these medications areadministered using eye droppers, which often require either the head tobe tilted back, the subject to lie down or provide downward traction onthe lower eyelid, or a combination of traction and tilting, since thedelivery mechanism typically relies on gravity for applying themedication. This is not only awkward, but involves a fair amount ofcoordination, flexibility and cooperation on the part of the subject toensure that the medication gets into the eye while avoiding poking theeye with the dropper tip. In current eye dropper bottles, the pointedapplicator tip poses the risk of poking the user in the eye, potentiallycausing physical damage to the eye, and further, exposing the tip tobacterial contamination due to contact with the eye. As such, thesubject runs the risk of contaminating the medication in the eye dropperbottle and subsequently infecting the eye. Additionally, a large volumeof the medication flows out of the eye or is washed away by the tearingreflex. As a result, this method of administration is also inaccurateand wasteful. Moreover, the eye dropper does not provide a satisfactoryway of controlling the amount of medication that is dispensed, nor doesit provide a way of ensuring that the medication that is dispensedactually lands on the eye and remains on the eye.

Eye droppers also provide no way of verifying compliance by a subject.Even if after a week of use the eye dropper bottle could be checked forthe total volume of medication dispensed, e.g., by weighing the bottle,this does not provide a record of day-to-day compliance. A subject mayhave missed one or more doses and overdosed on other occasions. Also,the poor precision with which eye droppers deliver drops to the eyemakes it difficult to determine whether the medication is actuallydelivered into the eye, even though it may have been dispensed.

The ability of piezoelectric droplet generation systems to eject fluidhas conventionally been largely limited by the piezoelectric materialproperties of the employed ceramic. For many years, an alternativepiezoelectric material system that is lead free with comparableproperties to lead based systems has been sought in order to meetworldwide regulations. This material system has yet to surface. Anejector system design which minimizes the dependency on piezoelectricmaterial properties to allow comparable ejection with inferior materialcharacteristics is thus highly desirable.

Accordingly, there is a need for a delivery device that delivers safe,suitable, and repeatable dosages to a subject for ophthalmic, topical,oral, nasal, or pulmonary use.

SUMMARY OF THE INVENTION

According to the present disclosure there is provided an ejector devicecomprising a housing, a reservoir having a volume of fluid containedwithin the housing, a fluid loading plate in fluid communication withthe fluid in the reservoir and an ejector mechanism in fluidcommunication with the fluid loading plate, wherein the fluid loadingplate provides fluid to a rear surface of the ejector mechanism, and theejector mechanism is configured to eject a stream of droplets of fluidthrough at least one opening. The fluid loading plate may be configuredto be placed in a parallel arrangement with the ejector mechanism so asto provide fluid to a rear ejection surface of the ejector mechanism.The ejector device of the disclosure is capable of delivering a definedvolume of fluid in the form of droplets having properties that affordadequate and repeatable high percentage deposition upon application.

In this regard, an important consideration according to the presentdisclosure is not only to be able to deliver the medication in an easierto use manner, e.g. by spraying a mist horizontally onto the surface tobe treated, but also to ensure that the medication is consistentlyprovided to the ejector or delivery mechanism in any orientation. Insome implementations, the ejector device is capable of ejecting a streamof droplets when the ejector device is tilted, even if tilted 180degrees upside-down.

In certain embodiments, the fluid loading plate may comprise a capillaryplate fluid delivery device for delivering fluid from a reservoir to anejector mechanism of an ejector device, and methods of use fordelivering safe, suitable, and repeatable dosages of fluids to a subjectfor ophthalmic, topical, oral, nasal, or pulmonary use. The capillaryplate may comprise a fluid reservoir interface, an ejector mechanisminterface, and one or more fluid channels for channeling fluid to theejector mechanism by one or more mechanisms, including capillary action.

In other embodiments, the fluid loading plate may comprise a punctureplate fluid delivery system for delivering fluid from a reservoir to anejector mechanism of an ejector device. The puncture plate fluiddelivery system, also referred to as a capillary/puncture plate fluiddelivery system, may include a capillary plate portion comprising afluid retention area between the puncture/capillary plate fluid deliverysystem and a rear surface of an ejector mechanism for channeling fluidto the ejector mechanism by one or more mechanisms, including capillaryaction, and at least one hollow puncture needle for transferring fluidfrom a reservoir to the fluid retention area.

In certain aspects, the puncture plate fluid delivery system may includea first and a second mating portion, wherein a reservoir is attached influid communication to the second mating portion, the second matingportion including a puncturable seal. The first mating portion may forma receptacle for the second mating portion, and may include the leastone hollow puncture needle for puncturing the puncturable seal. Thefirst mating portion and the at least one puncture needle may beintegrally formed. The puncturable seal included in the second matingportion may comprise a self-sealing silicone.

The reservoir, also referred to herein as an ampoule, may comprise acollapsible and flexible container. The reservoir may comprise acontainer and a lidding wherein the reservoir is configured so that thelidding and container form a volume capable of containing a fluid. Thereservoir may be configured to be partially collapsed (at sea level) andcapable of expanding to accommodate expansion of gas within the volumeand prevent leaks.

The ejector mechanism may comprise an ejector plate coupled to a dropletgenerator plate (referred to herein simply as a generator plate) and apiezoelectric actuator; the generator plate including a plurality ofopenings formed through its thickness, and the piezoelectric actuatorbeing operable to oscillate the ejector plate and thereby oscillate thegenerator plate at a frequency to generate a directed stream ofdroplets. The ejector plate may have a central open region aligned withthe generator plate, wherein the piezoelectric actuator is coupled to aperipheral region of the ejector plate so as not to obstruct theplurality of openings of the generator plate. The plurality of openingsof the generator plate may be disposed in a center region of thegenerator plate that is uncovered by the piezoelectric actuator andaligned with the central open region of the ejector plate. Thethree-dimensional geometry and shape of the openings, including orificediameter and capillary length, and spatial array on the generator platemay be controlled to optimize generation of the directed stream ofdroplets. The generator plate may be formed from a high modulus polymermaterial, for example, formed from a material selected from the groupconsisting of: ultrahigh molecular weight polyethylene (UHMWPE),polyimide, polyether ether ketone (PEEK), polyvinylidene fluoride(PVDF), and polyetherimide. The ejector mechanism may be configured toeject a stream of droplets having an average ejected droplet diametergreater than 15 microns, with the stream of droplets having lowentrained airflow such that the stream of droplets deposits on the eyeof the subject during use.

The ejector mechanism may have a centro-symmetric structure in which theejector plate includes symmetrically arranged mounting structures, witha symmetric configuration in which droplets are ejected from a centralregion of the symmetrical structure. The piezoelectric actuator mayinduce a resonance amplification of the generator plate coupled to theejector plate to provide for a greater variety of piezoelectricconstants. The ejector plate may be made of a high modulus polymericmaterial, and the piezoelectric actuator may be lead free, orsubstantially lead free.

The droplets may be formed in a distribution of sizes, each distributionhaving an average droplet size. The average droplet size may be in therange of about 15 microns to over 400 microns, e.g., greater than 20microns to about 400 microns, about 20 microns to about 200 microns,about 100 microns to about 200 microns, about 20 microns to about 80microns, about 25 microns to about 75 microns, about 30 microns to about60 microns, about 35 microns to about 55 microns, etc. However, theaverage droplet size may be as large as 2500 microns, depending on theintended application. Further, the droplets may have an average initialvelocity of about 0.5 m/s to about 100 m/s, e.g., about 0.5 m/s to about20 m/s, about 0.5 to about 10 m/s, about 1 m/s to about 5 m/s, about 1m/s to about 4 m/s, about 2 m/s, etc. As used herein, the ejecting sizeand the initial velocity are the size and initial velocity of thedroplets when the droplets leave the ejector plate. The stream ofdroplets directed at a target will result in deposition of a percentageof the mass of the droplets including their composition onto the target.

The ejector mechanism and fluid loading plate may be assembled to form aunit defining an ejector assembly, the ejector assembly comprising afluid loading plate in fluid communication with an ejector mechanismsuch that the fluid loading plate provides fluid to a rear surface ofthe ejector mechanism, the ejector mechanism being configured to eject astream of droplets. In certain embodiments, the ejector assembly mayfurther comprise a reservoir in fluid communication with the fluidloading plate.

The ejector device may further include an auto-closing system, whichgenerally reduces crystallization, evaporation, and contamination risk.The auto-closing system may include a user-activated slide-plate thatsealingly engages a gasket or seal formed to surround at least the holesin the generator plate, and which is slidable between an open positionin which the holes are exposed and a close position in which the holesare covered by the slide-plate. The slide-plate may be biased toward itsclosed position by means of a spring. The slide plate may include anopening configured to coincide with the holes in the generator platewhen the slide-plate is in its open position. Means may be included inthe auto-closing system to ensure that the slide plate presses withsufficient pressure against the seal when in the closed position.

Further, according to the disclosure, there is provided an auto-closingsystem for a droplet ejection device which generally reducescrystallization, evaporation, and contamination risk.

Still further, according to the disclosure, there is provided a methodfor the fabrication of a generator plate for ejecting high viscosityfluids suitable for ophthalmic, topical, oral, nasal, or pulmonary use,comprising laser micromachining of materials to form three-dimensionalopenings through the thickness of the material, each of the openingsdefining an entrance cavity and a capillary channel, wherein the openingcomprises an overall pitch length.

Still further, according to the disclosure there is provided a method ofdelivering a volume of ophthalmic fluid to an eye of a subject, themethod comprising ejecting a directed stream of droplets of anophthalmic fluid contained in a reservoir from openings of an ejectorplate, the droplets in the directed stream having an average ejectingdiameter in the range of 5-2500 microns, e.g., 20-400 microns, e.g.,20-200 microns, and including but not limited to a range of 100-200,etc., and an average initial velocity in the range of 0.5-100 m/s, e.g.,1-100 m/s, e.g., 2-20 m/s.

These and other aspects of the invention will become apparent to one ofskill in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a three-dimensional exploded view of the mechanical parts ofone embodiment of an ejector device of the disclosure;

FIG. 2 is front view of one embodiment of a an ejector device of thedisclosure;

FIG. 3 shows one embodiment of a reservoir of the disclosure;

FIG. 4 shows another embodiment of a reservoir of the disclosure;

FIG. 5 illustrates the variation of atmospheric pressure (p) withaltitude (h);

FIGS. 6A-6D illustrate various embodiments of components of a reservoiraccording to one embodiment of the disclosure;

FIG. 7 illustrates a form, fill and seal process for generation ofreservoirs in accordance with one embodiment of the disclosure;

FIG. 8 shows an embodiment of a reservoir, fluid loading plate andejector plate in accordance with an aspect of the disclosure,illustrating the direction of droplet ejection relative to attitudeangle.

FIGS. 9A-9B show an embodiment of a testing apparatus for measuringdifferential pressure induced leakage in an embodiment of a reservoir,fluid loading plate and ejector assembly (FIG. 9A, side view, FIG. 9B,top view) in accordance with an aspect of the disclosure;

FIGS. 10A-10E illustrate reservoir expansion following a decrease inpressure and a determination of the leak point pressure for embodimentsof a reservoir, fluid loading plate and ejector assembly, in accordancewith aspects of the disclosure;

FIG. 11 illustrates the effect of the volume V_(gas) expressed as apercentage of V_(t) on the differential leakage pressure value fordifferent embodiments of a reservoir, fluid loading plate and ejectorassembly in accordance with aspects of the disclosure.

FIG. 12 illustrates the loss of mass from reservoirs (ampoules) overtime, in accordance with an aspect of the disclosure;

FIGS. 13A-13B illustrate the attitude insensitivity of an embodiment ofthe disclosure having a collapsible and flexible reservoir (ampoule) inFIG. 13B, compared to an embodiment of the disclosure having a hardreservoir in FIG. 13A;

FIGS. 14A-14C show one embodiment of a capillary plate of thedisclosure;

FIGS. 15A-15C show one embodiment of an ejector mechanism in relation toan embodiment of a capillary plate of the disclosure;

FIGS. 16A-16B illustrate the relationship between plate separation andwater height in vertical parallel plates;

FIGS. 17A-17B show an embodiment of a capillary plate of the disclosure;

FIG. 18 shows the effect of resonant frequency on mass deposition ofwater with and without a capillary plate;

FIG. 19 illustrates that an increased water height behind an ejectorplate in the presence of a capillary plate leads to an increased massloading effect at a particular frequency;

FIG. 20 illustrates the downward shift in frequency associated with acapillary plate used with the delivery of various fluids;

FIG. 21 illustrates the reduction in mass loading for fluids ofincreasing density and viscosity;

FIG. 22 illustrates the attitude insensitivity of an ejector device thatincludes a capillary plate;

FIG. 23 shows the main components of one embodiment of an ejectorassembly including a puncture/capillary plate system with reservoir andejector mechanism according to the disclosure;

FIGS. 24A-24B show three dimensional front and back view of thecomponents of FIG. 23 in assembled form;

FIGS. 25A-25B show a detailed back and front view of one embodiment ofan ejector mechanism of the disclosure;

FIG. 26 is a schematic representation outlining fluid flow through apuncture plate system of the disclosure;

FIG. 27 is a schematic representation of a puncture plate system of thedisclosure showing the Venturi effect;

FIG. 28 illustrates the principles of Bernoulli's equation;

FIG. 29 illustrates the principles of hydrostatic pressure;

FIG. 30 shows schematic representations of different reservoirconfigurations of the disclosure;

FIG. 31 shows schematic representations of further reservoirconfigurations of the disclosure;

FIGS. 32A-32B show three dimensional pictures and side view and frontview drawings of two collapsible reservoir embodiments of thedisclosure;

FIG. 33 shows a back view of one embodiment of a blow-fill-sealreservoir and puncture plate of the disclosure;

FIGS. 34A-34B show side views of two blow-fill-seal reservoir andpuncture plate system embodiments of the disclosure;

FIG. 35 shows different form-fill-seal reservoir embodiments of thedisclosure;

FIG. 36 shows aspects of an apparatus and set-up to determine the amountof negative pressure that different reservoir configurations exert asthey are removing fluid;

FIG. 37 shows additional aspects of an apparatus and set-up to determinethe amount of negative pressure that different reservoir configurationsexert as they are removing fluid;

FIG. 38 shows the mass per spray and total spray (spray downperformance) of a non-collapse biased reservoir embodiment withsubstantial crease formation of the disclosure;

FIG. 39 shows the mass per spray and total spray (spray downperformance) of various blow-fill-seal reservoir embodiments of thedisclosure;

FIG. 40 shows two runs of a mass per spray and total spray (spray downperformance) of an LTS/collapse-biased self-sealing RW weld reservoirembodiment of the disclosure;

FIG. 41 shows the pull down performance for select round LTS ampouledesigns from FIG. 35.

FIG. 42 shows the mechanism involved in inverted spray using a round LTSreservoir;

FIG. 43 shows the actual spray down performance results of an LTSreservoir embodiment sprayed down in a complete puncture system upsidedown of the disclosure;

FIG. 44 shows the spray down performance of another puncture plateconfiguration with an embodiment of an embodiment an IV bag reservoir ofthe disclosure;

FIG. 45 shows the spray down performance of two different puncture plateconfigurations with an embodiment of an IV bag reservoir of thedisclosure in different orientations and with different spraydirections;

FIG. 46 shows the spray down performance of one embodiment of a punctureplate configuration with an embodiment of an IV bag reservoir of thedisclosure in different orientations and with different spray directionsand different puncture plate vent opening options;

FIG. 47 shows schematically the relationship between capillary effectand hydrostatic pressure of the reservoir;

FIG. 48 shows capillary pressure for various sized half droplets ofwater;

FIG. 49 shows capillary pressure for various sized half droplets oflatanaprost;

FIG. 50 shows capillary rise for various fluid types having differentcontact angle values;

FIG. 51 shows capillary rise for saline in a capillary channel made ofdifferent types of materials;

FIG. 52 shows fluid rise levels between puncture plate and ejector platefor an exemplary material;

FIG. 53 shows fluid rise levels between puncture plate and ejector plateover time;

FIG. 54 shows a test set-up to test for fluid leaking out of capillaryrise hole under different fluid fill locations;

FIG. 55A shows a cross-sectional view of one embodiment of an ejectorassembly of the disclosure;

FIG. 55B shows a three dimensional view of one embodiment of an ejectormechanism of the disclosure;

FIG. 55C shows a front view of one embodiment of a centro-symmetricejector mechanism of the disclosure;

FIG. 55D shows a dismantled view of one embodiment of an ejectormechanism of the disclosure;

FIG. 56 shows the nomenclature of the axis numbering convention forpiezoelectric effects;

FIG. 57 shows modes of operation of an active region of one embodimentof generator plate, and digital holographic microscopy images ofoscillation of the generator plate;

FIG. 58 illustrates a comparison of mass ejection for PZT and BaTiO₃(lead free) piezoelectric actuator materials using an ejector assemblywith an inside mounted piezoelectric actuator according to oneembodiment of the disclosure;

FIG. 59 illustrates a comparison of mass ejection for PZT and BaTiO₃(lead free) piezoelectric actuator materials using an ejector assemblywith an edge mounted piezoelectric actuator according to anotherembodiment of the disclosure;

FIG. 60 shows a three dimensional transparent view of one embodiment ofan ejector assembly with auto-closing system of the disclosure;

FIG. 61 shows the ejector assembly with auto-closing system of FIG. 60in a dismantled state;

FIG. 62 is a sectional side view of part of the ejector assembly withauto-closing system of FIG. 60;

FIG. 63 shows three-dimensional front view of a sliding unit of theself-closing system of FIG. 60;

FIG. 64 shows three-dimensional back view of the sliding unit of FIG.63;

FIG. 65 is a front view of the auto-closing unit of FIG. 60 in a closedposition;

FIG. 66 is a sectional side view of the auto-closing unit of FIG. 60 ina closed position;

FIG. 67 is a front view of the auto-closing unit of FIG. 60 in an openposition;

FIG. 68 is a sectional side view of the auto-closing unit of FIG. 60 inan open position;

FIGS. 69A-69C show transmission light microscopy images over time of amesh screen of a generator plate in which the system was not providedwith a capillary plate, and

FIGS. 70A-70C show transmission light microscopy images over time of amesh screen of a generator plate in which the system was provided with acapillary plate.

DETAILED DESCRIPTION

The present application relates to ejector devices for delivering fluidto a surface as an ejected stream of droplets. The ejector device mayfor example be as described in U.S. Provisional Application Nos.61/569,739, 61/636,559, 61/636,565, 61/636,568, 61/642,838, 61/642,867,61/643,150 and 61/584,060, and in U.S. patent application Ser. Nos.13/184,446, 13/184,468 and 13/184,484, the contents of which areincorporated herein by reference.

The ejector device of the present disclosure may, for example, beuseful, in the delivery of fluid for ophthalmic, topical, oral, nasal,or pulmonary use. However, the disclosure is not so limited, and may beuseful with any ejector devices (e.g., printer devices, etc.).

In certain embodiments, the ejector device may comprise a housing, areservoir disposed within the housing for receiving a volume of fluid, afluid loading plate, and an, ejector mechanism configured to eject oneor more streams of droplets of a fluid, wherein the reservoir is influid communication with the fluid loading plate, which is in fluidcommunication with the ejector mechanism such that the fluid loadingplate provides fluid to a rear surface of the ejector plate.

Thus the present disclosure generally relates to an ejector device forejecting a fluid onto a surface e.g., the ejection of ophthalmic fluidonto the eye of a patient. One embodiment components of the ejectordevice will be described broadly with respect to FIG. 1, whereafter someof the elements making up the device will be discussed in greaterdetail. It will however be appreciated that the application is notlimited to the particular embodiments described herein but includesvariations and different combinations of the elements making up theejector device.

For purposes of this application, fluid includes, without limitation,suspensions or emulsions which have viscosities in a range capable ofdroplet formation using an ejector mechanism.

FIG. 1 shows an exploded view of one embodiment of internal componentsof an ejector device 100 of the present disclosure, and includes areservoir 102, which in this embodiment is a flexible reservoir madeusing a self-sealing RF weld technique. The reservoir 102 is placed intofluid communication with a fluid loading plate 104 by means ofpuncturable seal mating 106. The fluid loading plate supplies the fluidfrom the reservoir to the rear face of an ejector mechanism 108 by,e.g., capillary action. The ejector in this embodiment comprises a piezoejector mechanism configured to generate a controllable stream ofdroplets of fluid. While the present embodiment describes a fluidloading plate 104, which is also discussed in greater detail below,other configurations may be adopted for channeling fluid by capillaryaction from the reservoir to the ejector mechanism. In order to limitevaporation, crystallization and contamination of the fluid, anauto-closing system 110 is mounted in front of the ejector mechanism108. A bracket 112 for supporting a housing 114 for a targeting LED isconfigured to clip onto the front face of the auto-closing system 110.

As shown in FIG. 2, in certain embodiments, the mechanical components ofthe ejector device may be mounted inside a removable top section 200 ofa housing 202, which mates with lower hand-grip portion 204. Theelectronics for controlling the ejection of fluid and power source maybe housed inside the lower hand-grip portion 204 of the housing 202.

The reservoir or ampoule 102 for use with the ejector device 100 maycomprise a flexible, or a hard, non-flexible reservoir. In certainembodiments, the reservoir comprises a collapsible and flexiblereservoir 102 disposed within the top section 200 of the housing 202,and contains or is adapted to receive a volume of fluid. Different typesof flexible reservoirs made using different techniques are contemplatedby the present disclosure, including self-sealing, radio frequency (RF)weld reservoirs as shown in FIG. 1. Alternatively, a blow-fill-sealtechnique can be used to form a similar configuration reservoir as shownin FIG. 3, or a form-fill-seal technique can be used to provide areservoir such as that shown in FIG. 4. As will become clearer from thediscussion below, the particular configuration of the reservoir may varyfrom one embodiment to the next. For example, the shape of theform-fill-seal reservoirs is not limited to that shown in FIG. 4.

With reference to FIG. 5, atmospheric pressure varies with altitude.Specifically, as the altitude increases, the pressure decreases. Inaccordance with Boyle's Law, the volume of a gas increases as thepressure decreases. Similarly, Charles' Law provides that as thetemperature increases, so does the volume of a gas. In contrast, liquidsgenerally have small changes in volume in response to changes inpressure and temperature, water being a notable exception which expandswhen cooled from 4° C. to 0° C. Thus while a liquid in a reservoir willchange little when the pressure and temperature conditions change, areservoir having a volume of liquid and also a volume of gas must bedesigned to accommodate decreases in pressure and increases intemperature. In many cases, the greater concern arises from changes inpressure, causing significant volume changes in the gas. Changes inaltitude are a common cause of changes in pressure and therefore in thevolume of gases.

Without intending to be limited by theory, a change in atmosphericpressure due to changes in altitude can be determined according to thefollowing equation:

${p = {p_{0} \cdot \left( {1 - \frac{L \cdot h}{T_{0}}} \right)^{\frac{g \cdot M}{R \cdot L}}}},$

Where:

Parameter Description Value p₀ sea level standard 101325 Pascal (Pa)atmospheric pressure L Temperature lapse rate 0.0065° Kelvin (K)/meter(m) T₀ sea level standard 288.15° K temperature g Earth-surfacegravitational 9.80665 m/sec (s) acceleration M molar mass of dry air0.0289644 kg/mol R Universal gas constant 8.31447 Joule (J)/(mol ° K)

An ampoule or reservoir, or a device containing the ampoule or reservoirmay, according to the disclosure, be transported in an airplane or to ageographic location high above sea level. As discussed, such changes canlead to pressure differentials from sea level that can lead to leakagefrom orifices of an ejector device. For example, cabins in an airplanecan be pressurized for altitudes from 6000 ft. to 8000 ft. Thecorresponding pressure differential from sea level is 20 to 29 kPa,respectively Ampoules that are not capable of accommodating for thispressure differential by expanding often lead to pressure buildup withinthe ampoule and subsequent fluid leakage from the device. As usedherein, “ambient pressure” refers to the air pressure to which thereservoir, ampoule or the device having a reservoir or ampoule isexposed to. As used herein, “pressure differential” refers to the airpressure difference between the ambient pressure and the standard airpressure at sea level (101325 Pascal (Pa)). Thus, the reduced pressureas found in a plane is the ambient pressure and the pressuredifferential is the difference between the ambient pressure and thestandard pressure at sea level (e.g., about 20 kPa at 6000 ft).Similarly, the pressure differential at an altitude above sea level isthe difference between the standard pressure at sea level (101325 Pascal(Pa)) and the ambient pressure at that altitude.

In other embodiments, the reservoir or ampoule may be a hard reservoirdesigned to accommodate expansion of any gas therein. In someembodiments, the expansion may be suppressed by providing a pressurizedenclosure. In other embodiments, leakage may be suppressed by sealingany orifice present on the reservoir.

With reference to FIGS. 6A to 6D, in certain embodiments, the reservoir(in this case a form-fill-seal reservoir) may comprise an ampoule havingthree components, a lidding 601, a container 602, and optionally astiffening ring 603. In some embodiments, the lidding 601 is sealed tothe container 602 to form an enclosed impermeable container. In anembodiment, the sealed impermeable combination of lidding 601 andcontainer 602 provides for storage of the liquid. In other embodiments,the container 602 forms a flexible reservoir that can accommodate theexpansion of a gas contained with and trapped by the reservoir. In otherembodiments, the reservoir may be formed of non-pliable materials tomake a stiff reservoir.

In some aspects according to the present disclosure, the ampoule orreservoir may be assembled from multiple components so that theproperties of lidding 601, container 602, and stiffening ring 603 may beadapted according to the needs of the device's application. In otherembodiments, the container 602 and stiffening ring 603 may be formedtogether, and lidding 601 applied following addition of a desired fluid.In an embodiment, the sealed impermeable combination of lidding 601 andcontainer 602 may be formed separately. In certain embodiments, thelidding 601 may be puncturable.

In certain embodiments, the shape and size of the ampoule or reservoirmay be selected according to the needs of the intended use. In anon-limiting example, a fluid for ophthalmic use may be required by aperson in need for a short treatment time, and thus may require fewerdoses. Where few doses are indicated, the shape and size of the ampoulemay be scaled appropriately to avoid unnecessary waste. In otheraspects, large volumes may be indicated where the fluid is required overa long period of time, or may require multiple daily doses.

The volume 610 may be controlled by varying the depth 607, the diameter604, and the shape 609. In some aspects, for example for pulmonary use,the diameter 604 may be more than 1 cm in diameter. In another aspect,the diameter may be 1.5 cm. In a further embodiment, the diameter may befrom 1 to 3 cm. In another embodiment the diameter may be between 1 and4 cm, or 1 and 5 cm. In other embodiments, the diameter 604 may be 3 cmor more, 4 cm or more, 5 cm or more, 6 cm or more, or 7 cm or more. Inother embodiments, the diameter may be configured for a device, forexample, for ophthalmic applications. For example, the diameter 604 maybe 20 mm or less. In other embodiments, the diameter 604 may be 19 mm orless. In another embodiment, the diameter 604 may be 18 mm or less. Inyet another embodiment, the diameter 604 may be 17 mm or less. In anembodiment, the diameter 604 may be 16 mm or less. In other embodimentsof the present disclosure, the diameter 604 may be from 18 to 19 mm. Inanother embodiment, the diameter may be from 15 to 20 mm, 16 to 20 mm,17 to 20 mm, 18 to 20 mm, or 19 to 20 mm. In other embodiments, thediameter 604 may be from 15 to 19 mm, 16 to 19 mm, 17 to 19 mm, or 18 to19 mm.

In certain embodiments according the present disclosure, the shape 609of the ampoule may be modified to increase or decrease the volume inview of the diameter 604. In some embodiments, the shape 609 may beconfigured so that the diameter decreases toward the closed end of thecontainer along the depth 607. In certain aspects, the decreasingdiameter may provide for removal of a mold. Design and manufacture ofmolds to form ampoules according to the present invention having acontainer 602 are known in the art.

In certain embodiments of the present disclosure, the ampoule maycomprise a stiffening ring 603 configured to add stability to thecontainer 602. In some embodiments, the container 602 may be flexibleand a stiffening ring 603 may provide for connection to the devices orhousings according to the present disclosure. The thickness 606 and thediameter 605 may be determined based on the diameter 604 of the shapedcontainer 602. In an aspect, the thickness 606 may be determinedaccording to the material of stiffening ring 603.

The sealed combination of lidding 601 and container 602, and optionalstiffening ring form an ampoule suitable for holding and storing a fluidfor ophthalmic, topical, oral, nasal, or pulmonary use until insertionof the ampoule into an ejector device or ejector device housing. In someembodiments, the sealed ampoule may be suitable for short-term storageof a fluid for ophthalmic, topical, oral, nasal, or pulmonary use. Inother embodiments, the sealed ampoule may be suitable for long termstorage of a fluid for ophthalmic, topical, oral, nasal, or pulmonaryuse.

In certain implementations, the sealed fluid containing ampoule may bestored without loss or degradation of the fluid for 1 week. In otherembodiments, the sealed ampoule may be stored for more than 1 week. Insome embodiments, the sealed ampoule may suitable for short term storageincluding 2 weeks, 3 weeks, or one month. In certain implementation, thesealed ampoule may be stored for a month.

In certain implementations, the sealed fluid containing ampoule may bestored for longer periods without significant loss or degradation. Inother embodiments, the sealed fluid containing ampoule may be stored formore than one month. In other embodiments, the sealed ampoule may bestored for more than two months. In some embodiments, the sealed ampoulemay be suitable for long-term storage including three months, fourmonths, or more. In certain implementations, the sealed ampoule may bestored for 5 months. In other embodiments, the sealed ampoule may bestored for 6 months. In some embodiments, the sealed ampoule maysuitable for long-term storage including 7 months, 8 months, or more. Incertain implementations, the sealed ampoule may be stored for 9 months.In certain implementations, the sealed ampoule may be stored for 10months. In other embodiments, the sealed ampoule may be stored for 11months. In some embodiments, the sealed ampoule may be suitable forlong-term storage including 12 months, or more. In certainimplementations, the sealed ampoule may be stored for 1.5 years. In yetother implementations, the sealed fluid filled ampoule may be stored formore than 1.5 years.

The lidding 601, container 602, and stiffening ring 603 may be formedfrom any suitable materials for use in the intended application. By wayof example, in ophthalmic applications, any suitable material for use inpharmaceutical ophthalmic applications may be used, such as polymermaterials that do not chemically react with or adsorb fluids to bedelivered. In other aspects, the surfaces of the lidding 601, container602, and stiffening ring 603 that are exposed to the fluid to bedelivered may be formed from materials that provide desired surfaceproperties, including for example hydrophobicity, hydrophilicity,non-reactivity, stability, etc. Examples of materials suitable for thelidding 601 and container 602 include materials presented in, but notlimited by, Table 1.

TABLE 1 Example lidding and container materials Manufacturer ProductName Description Sealed Air Nexcel Latitude PE based coextruded filmML29xxC Sealed Air Nexcel M2930 Sealed Air Nexcel MF513 Barrier Medicalfilm with clear oxygen barrier Rollprint Triad “C” Extrusion laminatedcomposite of polyester, polyethylene, aluminum foil and modifiedpolyolefin sealant Alcan Pouch laminate High barrier coextrudedPackaging Product Code composite of PET, adhesive, Pharmaceutical 92036aluminum, polyethylene Packaging Inc. Texas SV-300X 3 mil nylon, EVOH,poly coex Technologies SAFC Bioeaze ethyl vinyl acetate film BiosciencesWinpak DF15YG2 Peelable Al-foil based (Al/PE) Winpak WCS100 Flexiblepackaging laminate composed of PET, LDPE Al, and coex

In some embodiments according to the present disclosure, the materialfor container 602 may be selected for properties consistent with anFDA-approved medical device. Materials may be selected by methods andcriteria known in the art, for example, ISO 10993-5, BiologicalEvaluation of Medical Devices—Part 5 US Pharmacopeia 32, BiologicalReactivity Tests, In Vitro; ISO 13485, Medical Device Quality ManagementSystem; and ISO 17025, General Requirements for the Competence ofTesting and Calibration Labs. For example, the container 602 may be anon-cytotoxic film such as ML29xxC available from Sealed Air.

According the present disclosure, material for container 602 may be apolymer. In certain embodiments the polymer may be a layered polymer. Inother embodiments, the polymer may be a coextruded forming film. Incertain embodiments, the polymer may be a polymer for use in medicaldevices. In one example according to the present disclosure, the filmmay be a polyethylene-based coextruded forming film. In certainembodiments, the polymer may be sterilized. In an aspect, the film maybe selected according to its ability to bond to other films. In oneexample, the other film may be Tyvek or other coated medical material.In an aspect, the film may be either clear or opaque. In another aspect,the film may be resistant to punctures. In yet another aspect, the filmmay be resistant to down-gauging.

In an aspect, the film may formable. Formable films according to thepresent disclosure may be selected according to the requirements of theapplication. In certain aspects, the film may be selected based on oneor more of the following criteria: thickness, Young's modulus,elongation, tensile strength, puncture force, tear and haze. In certainaspects, the flexibility of the film may provide for a collapsibleampoule. In an aspect, the collapsible ampoule may provide for theelimination of leakage upon changes of atmospheric pressure.

Examples of films compatible with devices and methods of the presentinvention include films provided in Table 2. According to the presentdisclosure, similar films may be selected based on the desiredproperties of Thickness, Young's modulus (MD), Elongation (MD), TensileStrength (MD), Puncture, Tear, and Haze.

TABLE 2 Example films of the present disclosure Sealed Air Nexcel ®Medical films: Latitude ML29xxC Unit ASTM 30 C. 45 C. 60 C. 70 C. 80 C.10 C. Thickness* micron 75 112.5 150 175 200 250 Young's modulus kg/cm²D882 4967 5059 4995 5002 5016 5023 (MD) Elongation (MD) % D882 280 340350 345 374 406 Tensile Strength kg/cm² D882 375 332 329 335 315 296(MD) Puncture N F1306 13.26 19.39 24.24 28.02 31.70 38.99 Tear g D1004718 1020 1360 1610 1817 2262 Haze % D1003 12 16 22 31 33 43

According to some implementations, lidding 601, container 602, andstiffening ring 603 may be a formed of materials suitable forsterilization. In some aspects lidding 601, container 602, andstiffening ring 603 may be sterilized together as a unit. In otheraspects, lidding 601, container 602, and stiffening ring 603 may besterilized separately, using one or more of the various methods ofsterilization known in the art. In certain aspects of the presentdisclosure, one or more sterilization methods may be combined, forexample chemical and irradiation methods as provided below.

In an aspect, lidding 601, container 602, and stiffening ring 603 may beformed from materials that are compatible with sterilization byirradiation. In an aspect, the material may be compatible withsterilization by gamma irradiation. In other aspect, the material may bechosen to be compatible with radiation such as electron beams, X-rays,or subatomic particles.

In another aspect, the container may be formed from materials that arecompatible with chemical methods of sterilization. In an embodiment, thematerial may be compatible with ethylene oxide (EtO) sterilization. Inanother embodiment, the material may be compatible with ozone (O₃)sterilization. In another embodiment, the material may be compatiblewith Ortho-phthalaldehyde (OPA). In a further embodiment, hydrogenperoxide may be used as a chemical sterilizing agent.

In some aspects according the present disclosure, lidding 601, container602, and stiffening ring 603 may be formed from materials that arecompatible with heat sterilization. In an embodiment, the heatsterilization compatible material may be resistant to dry heatsterilization. In another embodiment, the heat sterilization compatiblematerial may be compatible to moist heat sterilization. In some aspectsaccording the present disclosure, lidding 601, container 602, andstiffening ring 603 may be formed from materials that are compatiblewith Tyndalization.

In some aspects, the materials chosen for lidding 601, container 602,and stiffening ring 603 provide for long term storage of the liquid. Insome embodiments, the sealed ampoule may comprise impermeable materials.In certain aspects, the impermeability may be selected on the basis ofthe fluid. In one non-limiting example according to the presentdisclosure, the fluids for ophthalmic, topical, oral, nasal, orpulmonary use may require protection from light or air to maintainstability. In another non-limiting example according to the presentdisclosure, the fluids for ophthalmic, topical, oral, nasal, orpulmonary use may require protection from light and oxygen to maintainstability. In some embodiments, the materials may be impermeable togases. In an embodiment, the gas may be oxygen. In other embodiments,the material may be impermeable to light. In another embodiment, thematerial may be impermeable to gas, for example oxygen, and impermeableto light.

In an aspect according to the present disclosure, the container 602 andlidding 601 material may be selected to be stable for extended periods.As one aspect, in certain embodiments, one or more properties including,but not limited to, the tensile strength, the percent elongation, tearresistance and impact stability may be used to determine the stabilityof the material.

Referring to FIG. 7, containers containing a fluid of the presentinvention may be prepared using a form, fill and seal process as knownin the art. In certain embodiments, the entire process outlined in FIG.7 may be performed under sterile conditions in compliance withapplicable regulatory standards for medical devices and preparations. Inone embodiment, a film may be applied to a mold and then heated andvacuum formed to create a container of shape 609 and depth 607. Byvarying the shape 609, depth 607 and diameter 604, a container orampoule of a defined total volume (V_(t)) may be formed.

Once formed, the container (e.g., container 602 for example), may befilled with a fluid and a lidding applied to the filled container orampoules. In some embodiments and by way of example only, a seal isapplied to create a leak-proof closure. Other methods to attach and seala lidding to the container are known in the art. Following sealingindividual ampoules may be cut from the form. In other embodiments, thesealing and cutting can occur simultaneously. The final sealedcontainers or ampoules are then suitable for storage, shipping or use inan ejector devise. As mentioned above, the form-fill-seal processdiscussed in this embodiment is only one technique for forming andsealing containers are known in the art. Other techniques such asblow-fill-seal and self-sealing RF weld can also be used and do not makeuse of a lidding element.

In some embodiments of the current disclosure, the fluid (V_(f)) mayfill the entire volume of container 602 (e.g., V_(t)). In otherembodiments, the fluid may not completely fill the volume, leaving aspace (V_(ΔT)). In embodiments where the liquid volume V_(f) equalsV_(ΔT), applying a lidding may result in the entrapment of a volume ofgas V_(gas). In other embodiments, the volume of container 602 may bedecreased by crushing or deforming up to a volume to reduce the volumeby a volume (V_(r)). According the present disclosure, the volume of thesealed container or ampoule will be:

V _(t) =V _(f) +V _(gas) +V _(r) where

V _(ΔT) =V _(gas) +V _(r)

According to certain aspects of the present disclosure, the volume V_(r)provides a capability to the container to expand to volume Vt, andthereby reduce the tendency of the container to leak when employed in anejector device. Similar, the volume V_(r) can accommodate an expansionof a volume of an aqueous fluid when shipped or stored frozen or underconditions where the volume of liquid may expand. In other embodiments,V_(ΔT) may include both a volume of gas V_(gas) and a volume V_(r)whereby, the change in gas volume associated with changes in ambientpressure may be compensated and provide for the preparation of leak freeejector devices. Similarly, the volume V_(r) also provides for anexpansion of gas of volume V_(exp) that may occur during shipping orstorage under conditions of lower ambient pressure.

In certain aspects according the present disclosure, the container maycontain a volume of gas V_(gas). In an aspect, the gas may be air. In anaspect, the gas may be air that has been depleted of oxygen. In otheraspects the gas may be a non-reactive gas. In an aspect, the gas may benitrogen. In another aspect, the gas may be a noble gas such as heliumor argon. In other aspects, the gas may be CO₂. Any gas may beaccommodated according to the present disclosure.

In certain embodiments of the disclosure, the reservoirs provide forattitude insensitivity of ejector devices. In an aspect the reservoirincludes a flexible container. Specifically, as provided by certainaspects of the present disclosure, the reservoir provides a consistentamount of fluid to the ejector mechanism, regardless of the fluid leveland device orientation. In some aspects, an ampoule or reservoir influid communication with an ejector mechanism provides a consistent flowof fluid to the rear surface of the ejector mechanism so that aconsistent volume of fluid is ejected as droplets. In another aspect,the reservoir or ampoule is in fluid communication with a capillaryplate that provides for consistent supply and delivery of fluid in acapillary fluid loading area at a rear ejection surface of an ejectormechanism. The ampoule provides for attitude insensitivity of theejector device and a resistance to leakage as the ambient pressure isdecreased relative to the standard pressure at sea level. Thus thecombination of ampoule, capillary plate and ejector mechanism provideboth reduced attitude and altitude sensitivity to the device so that aconsistent volume of droplets is delivered.

Referring to FIG. 8, a device of the present disclosure ejects fluid ina direction 804, perpendicular to the direction of gravity 805. In anaspect of the present disclosure, the combination of ampoule 803 andfluid loading plate 802 provide for a consistent flow of fluid to theejector plate 801 as the attitude angle theta (θ) is change. Forexample, as the attitude is increased, the combination provides forcontinued consistent flow of fluid. Accordingly, according to aspects ofthe present invention, the device continues to dispense droplets in thedirection 804. In an aspect of the present disclosure, the attitudeangle theta (θ) may be arbitrarily increased or decreased whilemaintaining a consistent flow of fluid to the ejector plate 801. Forinstance, the attitude angle theta (θ) may be more or less than 45°.Thus, the attitude angle theta (θ) may be between 0 and 45° or may bebetween 45° and 90°. The attitude angle theta (θ) may also be 90°. Theattitude angle theta (θ) may also be 180° or may be between 0 and 180°.

In certain implementations according to the present invention, thecontainers are flexible containers having a total volume V_(t) andcontain a volume of liquid V_(f) and a volume of gas V_(gas), and have aexpandable volume V_(r). In certain aspects, the expandable volume V_(r)provides for and accommodates the expansion of the gas ΔV_(gas) due tochanges in pressure while not resulting in an increase in pressurewithin the container. Thus, while in transit for example, an expansionof ΔV_(gas) does not cause the container to leak. Similarly, theexpansion of an aqueous fluid upon freezing can be similarlyaccommodated.

Many implementations of the invention have been disclosed. Thisdisclosure contemplates combining any of the features of oneimplementation with the features of one or more of the otherimplementations. For example, any of the ejector mechanisms or capillaryplates can be used in combination with the container, as well as any ofthe housings or housing features, e.g., covers, supports, rests, lights,seals and gaskets, fill mechanisms, or alignment mechanisms. Furthervariations in any of the elements of any of the embodiments within thescope of ordinary skill are contemplated by this disclosure. Suchvariations include selection of materials, coatings, or methods ofmanufacturing. Other methods of fabrication known in the art and notexplicitly listed herein can be used to fabricate, test, repair, ormaintain the device.

Example 1: Measurement of Differential Pressure Leak Values

FIG. 9 shows an assembly that allows an assembly of container, fluidloading plate and ejector device to be tested for leakage as thepressure is decreased. The fluid filled container is mounted onto a leakpressure test apparatus which consists of an ampoule retaining mount(1), fluid loading plate (2), which delivers fluid behind the ejectorplate (3). The leak pressure test apparatus is placed within a vacuumchamber that is pumped by a mechanical pump suitable for attaining 2.75psi. At this pressure (2.75 psi) the measured pressure differentialbetween STP (13.23 psi) and the lowest measurable leakage pressure (2.75psi) is 10.5 psi, or 72.3 kPa. Leakage at this pressure is equivalent toa pressure differential encountered in traveling from sea level to31,000 feet. FIG. 9 also illustrates an aspect of the container having aV_(r) greater than zero. Thus, the container provides for expansion ofthe gas as the ambient pressure is decreased inside the vacuum chamber.Variation of the V_(r) can affect the leak pressure.

Table 3 provides the results of leak pressure testing through 40 umholes on a 12 mm deep (e.g., depth 607 of FIG. 6) flexible container.

TABLE 3 Leak pressure test through 40 um holes with 12 mm deep flexiblecontainer Experiment Delta P #: % Full (%) % Air Volume Delta P (psi)(kPa) 1 97.20 3.43 1.66 11.43 2 93.20 8.34 2.45 16.91 3 77.38 22.70 0.996.80 4 81.89 18.18 1.16 8.00 5 87.72 12.32 3.51 24.18 6 85.28 14.77 1.8012.41 7 81.17 18.90 1.89 13.05 8 73.31 26.79 1.00 6.89Table 4 provides the results of leak pressure testing through 20 umholes on a 20 mm deep flexible container.

TABLE 4 Leak pressure test through 20 um holes with 20 mm deep flexiblecontainer Start Experiment % Air Pressure Leak Delta P Delta P #: Volume(psi) Pressure (psi) (psi) (kPa): 1 3.13 13.23 2.75 10.48 72.26 2 3.1313.26 2.95 10.31 71.09 3 15.63 13.26 6.40 6.86 47.30 4 9.38 13.26 5.957.31 50.40 5 6.25 13.25 3.75 9.50 65.50 6 12.50 13.25 5.95 7.30 50.33 79.38 13.25 5.25 8.00 55.16Table 5 provides the results of leak pressure testing through 40 umholes on a 20 mm deep flexible container.

TABLE 5 Leak pressure test on 20 mm flexible container with 40 um holesStart Experiment % Air Pressure Leak Pressure Delta P Delta P #: Volume(psi) (psi) (psi) (kPa): 1 2.3 13.28 2.75 10.53 72.6 2 6.3 13.28 3.1810.1 69.6 3 9.4 13.28 5.2 8.08 55.7 4 12.5 13.28 5.5 7.78 53.6 5 15.613.28 5.9 7.38 50.9 6 18.8 13.27 6.15 7.12 49.1 7 21.9 13.27 6.35 6.9247.7Table 6 provides the results of leak pressure testing through 40 umholes on a 20 mm deep hard container.

TABLE 6 Leak Pressure Test on Hard container with 40 um holes StartExperiment % Air Pressure Leak Pressure Delta P Delta P #: Volume (psi)(psi) (psi) (kPa): 1 12.5 13.25 12.85 0.4 2.8 2 4.2 13.25 12.75 0.5 3.44 29.2 13.25 12.75 0.5 3.4 5 37.5 13.25 12.7 0.55 3.8 8 20.8 13.25 12.720.53 3.7

FIG. 10 illustrates the results of container expansion as a mechanism ofpressure equalization. As tested in Example 1 and presented in Table 4,as the pressure is decreased, the gas expands, causing an expansion ofthe collapsed volume V_(r). As V_(gas) approaches the total volumeV_(ΔT) the tendency of the apparatus to leak increases. Smaller volumesof air are generally associated with lower leak point pressures. Delta Prepresents the pressure at which the combination begins to leak.

FIG. 11 graphically presents the results of leak pressure testing ofdifferent embodiments of the present disclosure. As shown, a hardreservoir leaks at low differential pressures that is independent of the% air volume (e.g., V_(air)/V_(t)). The 12 mm deep container (ampoule)requires higher differential pressures to induce leakage and a maximalpressure of about 25 is observed for about a 12% air volume. A 20 mmdeep container having either 40×160 um holes or 20×40 um holes, requiresthe highest differential pressures to cause leakage. In theseembodiments, the hole number and size were not distinguishable.

Example 2: Measurement of Mass Loss Over Time

FIG. 12 shows the mass loss from an ampoule (reservoir) over time todetermine the storage ability of ampoules (reservoirs) of the presentdisclosure. A series of reservoirs are stored for 72 days and the amountof mass determined. From a total volume of 3.5 ml, a total volume of 50μl escapes over the time period.

Experiment 3. Measurement of Ejection Volume at Different AttitudeAngles

FIG. 13 shows the ejection volume at differing attitude angles over arange of frequencies of a piezoelectric ejector device having either ahard reservoir or a flexible reservoir. The flexible ampoule designprovides more consistent ejection of fluid volume over a broaderfrequency range and fill level.

Although the foregoing describes various reservoir embodiments by way ofillustration and example, the skilled artisan will appreciate thatvarious changes and modifications may be practiced within the spirit andscope of the present application. As used herein, a reservoir may be anyobject suitable for holding a fluid. By way of example, the reservoirmay be made of any suitable material capable of containing a fluid.Reservoirs of the present disclosure may be rigid or flexible and thereservoirs of the present disclosure may further be collapsible. As usedherein, collapsible refers to a decrease in volume obtainable in areservoir achieved by squeezing, folding, crushing, compressing,vacuuming, or other manipulation, such that total volume enclosed aftercollapsing is less than a volume that could be enclosed in anon-collapsed container. A reservoir may be made of any suitablematerial that can formed into a volume capable of holding a volume offluid. Suitable materials, for example, may either be flexible or rigidand may be formable or pre-formed. As used herein a reservoir, by way ofexample, may be formed from a film.

In other aspects, a fluid loading plate of the disclosure may beintegrated into an ejector device between a reservoir and an ejectormechanism. In certain embodiments, the ejector device may be fordelivering a fluid to an eye of a subject, and may comprise a housing, areservoir disposed within the housing for receiving a volume of fluid,the reservoir being in fluid communication with a fluid loading plate,the fluid loading plate being in fluid communication with an ejectormechanism such that the fluid loading plate provides fluid to a rearejection surface of an ejector mechanism, wherein the ejector mechanismis configured to eject a stream of droplets of a fluid. The ejectormechanism may be configured to eject a stream of droplets having anaverage ejected droplet diameter greater than 15 microns, with thestream of droplets having low entrained airflow such that the stream ofdroplets deposits on the eye of the subject during use.

In certain embodiments, the ejector mechanism may comprise an ejectorplate and a piezoelectric actuator; the ejector plate including aplurality of openings formed through its thickness; and thepiezoelectric actuator being operable to oscillate the ejector plate ata frequency, and generate a directed stream of droplets. In certainaspects, the ejector plate may be formed from a high modulus polymermaterial.

In certain embodiments, the piezoelectric actuator is coupled to aperipheral region of the ejector plate so as not to obstruct theplurality of openings of the ejector plate. The plurality of openings ofthe ejector plate may be disposed in a center region of the plate thatis uncovered by the piezoelectric actuator. In certain embodiments, thethree-dimensional geometry and shape of the openings, including orificediameter and capillary length, and spatial array on the ejector platemay be controlled to optimize generation of the directed stream ofdroplets.

By way of example, the fluid loading plate may be integrated into anejector device or ejector assembly, or configured to interface with anejector mechanism as disclosed, for example, in the applications: U.S.Application No. 61/591,786, filed Jan. 27, 2012, entitled “High ModulusPolymeric Ejector Mechanism, Ejector Device, and Methods of Use”; U.S.Application No. 61/569,739, filed Dec. 12, 2011, entitled “EjectorMechanism, Ejector Device, and Methods of Use”; and U.S. applicationSer. No. 13/184,484, filed Jul. 15, 2011, entitled “Drop GeneratingDevice”, which applications are each herein incorporated by reference intheir entireties.

Many embodiments and implementations of the invention are disclosedherein. This disclosure contemplates combining any of the features ofone embodiment with the features of one or more of the otherembodiments. For example, any of the ejector mechanisms or reservoirscan be used in combination with the fluid loading plate, as well as anyof the housings or housing features discussed in the incorporatedreferences, e.g., covers, supports, rests, lights, seals and gaskets,fill mechanisms, or alignment mechanisms. Further variations on any ofthe elements of any of the aspects of the present disclosure that arewithin the scope of ordinary skill are contemplated by this disclosure.Such variations include selection of materials, coatings, or methods ofmanufacturing.

With reference to FIGS. 14A-14C, in one embodiment, the fluid loadingplate may comprise a capillary plate 1400 including a fluid reservoirinterface 1402, an ejector mechanism interface 1404, and one or morefluid openings 1406. If desired, the capillary plate 1400 may optionallyinclude a reservoir housing mating ring 1410 to facilitate connectionwith various reservoir housing configurations (not shown), as describedin U.S. application Ser. No. 13/184,484, filed Jul. 15, 2011, entitled“Drop Generating Device”, which is herein incorporated by reference inits entirety.

In addition, the capillary plate 1400 may optionally include fasteningclips 1412 on the housing mating ring 1410 to secure capillary plate1400 to a reservoir housing (not shown). Although exemplary clipconfigurations and positions are shown, different embodiments andpositions are envisioned and within the scope of the disclosure.Capillary plate 1400 may also include piercing projections 1414 on thefluid reservoir interface 1402 to facilitate opening of variousreservoir housing configurations (not shown). Again, although exemplarypiercing projections and positions are shown, different embodiments andpositions are envisioned and within the scope of the disclosure. Forinstance, the piercing projections may be sized and shaped so as not tohinder fluid flow through the one or more fluid openings 1406.

With reference to FIGS. 15A-15C, in certain embodiments, the ejectormechanism interface 1502 of the capillary plate 1500 is placed inparallel arrangement with a rear ejection surface 1506 of the ejectormechanism 1504 so as to form a separation 1508 between the capillaryplate and the ejector mechanism, and generate fluid flow 1510 betweenthe capillary plate 1500 and the ejector mechanism 1504 in the capillaryfluid loading area 1512 at the rear ejection surface of the ejectormechanism. This fluid flow 1510 allows the capillary plate 1500 toprovide fluid to the rear ejection surface 1506 of the ejector plate1514 of the ejector mechanism. The configuration of the capillary plateprovides for consistent supply and delivery of fluid in the capillaryfluid loading area at the rear ejection surface 1506 of the ejectorplate 1514. As a result, a consistent volume of droplets is generated bythe ejector mechanism, regardless of fluid level and device orientation(i.e., attitude).

With reference to FIGS. 16A and 16B, the fluid loading between theparallel surfaces of the capillary plate and the ejector plate isdependent upon distance d of the capillary plate separation. As is shownin FIG. 16A, plate separation of up to 1 mm provides adequate fluidloading (liquid height) in the capillary fluid loading area. In certainembodiments, a separation distance between the capillary plate and theejector mechanism of between about 0.2 mm and about 0.5 mm, moreparticularly between about 0.2 and about 0.4 mm, or more particularly of0.3 mm may be used.

Without intending to be limited by theory, general expressions forcapillary rise between two parallel surfaces are set out below:

${{\langle h\rangle} = \frac{\gamma_{lv}\left( {{\cos \left( \theta_{1} \right)} + {\cos \left( \theta_{2} \right)}} \right)}{pgd}};{h = \frac{2\gamma_{lv}{\cos (\theta)}}{pgd}}$

where:h is the liquid height;γ_(1v) is the liquid vapor surface tension in contact with a surface;θ is the contact angle between the fluid and the surface;ρ is density difference between fluid and vapor;g is acceleration of gravity; andd is the separation distance between surfaces.

The fluid loading plate may be formed from any suitable materials foruse in the intended application. By way of example, in ophthalmicapplications, any suitable material for use in pharmaceutical ophthalmicapplications may be used, such as polymeric materials that do notchemically react with or adsorb fluids to be delivered. In certainembodiments, the surfaces of the fluid loading plate that are exposed tothe fluid to be delivered may be formed from materials that providedesired surface properties, including hydrophilic/hydrophobicproperties, surface energy, etc., so as to facilitate wicking andcapillary action between the parallel surfaces. For example, see U.S.Pat. No. 5,200,248 to Thompson et al., which is herein incorporated byreference.

In certain embodiments, the fluid loading plate may be formed from asingle material, e.g., in a capillary plate embodiment. In otheraspects, the fluid loading plate may be a composite formed from morethan one material wherein the surfaces that are exposed to the fluid tobe delivered are selected so as to have desired surface properties. Byway of example, a capillary plate may be injection molded orthermoformed as a unitary piece or as separate pieces. If desired, oneor more reservoir mating surfaces may be separately formed, or formed asa unitary piece with other components of the capillary plate. Withoutintending to be limiting, and by way of example, materials include:polyamides including nylons such nylon-6, HDPE, polyesters,co-polyesters, polypropylene, and other suitable pharmaceutical gradehydrophilic polymers or polymeric structures.

The fluid loading plate may be sized and shaped in any suitable mannerso as to interface with the desired ejector mechanism such that fluid isprovided to and a suitable capillary fluid loading zone is formed at theejector mechanism interface between the capillary plate and the rearejector surface of the ejector mechanism. With reference to FIG. 17A and17B, one embodiment of a capillary plate 1700 is illustrated. Howeverthe sizes given in FIGS. 17A and 17B are for illustration purposes only,and the disclosure is not so limited. By way of example, capillary plate1700 may be generally square shaped and have an edge length of about 25mm. However, other shapes are envisioned, including generally circularconfigurations, etc. Four separated fluid openings 1706 are shown aboutan annular radius of about 4.70 mm, having a general opening width ofabout 2.50 mm and a spacing of about 2 mm. The thickness of the fluidflow portion of capillary plate 1700 (i.e., the portion of capillaryplate 1700 including fluid opening 1706) may be about 0.30 mm, and thethickness of the housing mating ring 1710 of capillary plate 1700 may beabout 2 mm Piercing projections 1714 may be, e.g., about 1.62 mm acrossand about 1.35 mm in length to provide for desired protrusion propertieswhile still allowing for fluid flow.

To assist in understanding the present invention, FIGS. 18-22 illustratevarious effects of the use of a fluid loading plate described herein onthe performance of an ejector device. The experiments described hereinshould not be construed as specifically limiting the invention and suchvariations of the invention, now known or later developed, which wouldbe within the purview of one skilled in the art are considered to fallwithin the scope of the invention as described herein and hereinafterclaimed.

More specifically, FIG. 18 illustrates the effects of a capillary plateon resonant frequency and mass deposition of water using a 160 micronthick NiCo ejector plate with 25 and 40 micron holes, showing a downwardshift in frequency. FIG. 19 illustrates that as the density (andtherefore the mass) of a fluid in a resonant system (such as thecapillary region behind the ejector plate) increases, so there is adownward shift in the resonant frequency. FIG. 20 illustrates thedownward shift in frequency associated with a capillary plate used withthe delivery of various fluids using a 160 micron thick NiCO ejectorplate with 25 and 40 micron holes. FIG. 21 illustrates both a reductionin resonant frequency and amplitude of the resonant structure as thedensity (φ and viscosity (η) of the fluid in the resonant system areincreased. By way of example, and not necessarily related to theparticular values in the graph of FIG. 21, the densities and viscositiesof water, ethanol and propylene glycol are given in the table below thegraph. As shown in FIGS. 18-21, the presence of a capillary plate leadsto an overall shift in resonance frequency, to lower frequencies. Theshift in volume sprayed for liquids is a consequence of increaseddensity and viscosity, (water, ethanol, and propylene glycol).

FIG. 22 illustrates the attitude insensitivity of an ejector device thatincludes a capillary plate. As shown, volume (mass) delivered isrelatively insensitive to ejector device orientation. This insures aconstant delivery and supply of fluid behind the ejector plate. As aresult, a consistent volume of droplets is formed and sprayed by theejector mechanism, regardless of fluid level and device orientation.

In other embodiments, the fluid loading plate may comprise a punctureplate fluid delivery system, also referred to as a capillary/punctureplate fluid delivery system, which is configured to deliver fluid fromthe reservoir to a fluid retention area at the back of the ejectormechanism for delivery as a directed stream of droplets viapiezoelectric ejection. Without intending to be limited by theory, thepuncture plate system may utilize one or more of hydrostatic pressure,capillary pressure, geometrical pressure gradients (Venturi effect), andair exhaustion.

One embodiment of a puncture plate fluid delivery system and itsoperation is shown in FIGS. 23-27. FIGS. 23A and B show a front view anda back view, respectively, of an ejector mechanism 2300 with 5 riseholes 2302. As shown in front view in FIG. 23C and in back view in FIG.23D, the puncture plate fluid delivery system may include a capillaryplate portion comprising a fluid retention area between thepuncture/capillary plate fluid delivery system and a rear surface of anejector mechanism for channeling fluid to the ejector mechanism by oneor more mechanisms, including capillary action, and at least one hollowpuncture needle for transferring fluid from a reservoir to the fluidretention area. In this embodiment, 6 hollow puncture needles 2306extend from the back surface of the capillary/puncture plate, thechannels through the needles extending through to the front face of thecapillary plate 2304 as shown by the holes 2308. The needles 2306 aresurrounded by a wall 2310 defining a receptacle for a fitment 2312(shown in FIG. 23E together with a self-sealing silicone sealing element2314 that is housed in the fitment 2312).

Initially, the fluid containing reservoir or ampoule 2316 (these termsare used interchangeably herein) is connected to the fitment and is influid communication with a secondary reservoir defined by the fitmentand the silicone sealing element 2314. The capillary plate 2304 is, inturn, attached to and in fluid communication with the ejector mechanism2300. However, prior to use, the puncture plate and ejector mechanism2300 may be provided in a disconnected state from the fitment 2312 andreservoir 2316 to prevent fluid exchange. During the initial stage ofconnection the hollow puncture needles 2302 shown on the back of thepuncture plate image in FIG. 23D are partially inserted into theself-sealing silicone puncture gasket or grommet 2314 that rests insidethe fitment 2312. The secondary reservoir formed in the fitment 2312 isconstantly open to the fluid in the primary ampoule/reservoir 2316. Atthis stage, fluid from the primary reservoir that has moved into thesecondary reservoir of the fitment 2312 does not enter into the hollowpuncture needles 2306, however, due to the barrier created by theself-sealing silicone gasket material 2314.

Puncture is accomplished by pressing the puncture plate needles all theway through the gasket 2314 into the fluid filled fitment by forcing theneedles through the silicone gasket. This may occur, e.g., when thefitment snap-fits (indicated by a clicking sound) into the receptacle2310 of the puncture plate 2304. A seal is maintained after puncturebecause the silicone gasket 2314 is a compliant and self-sealingmaterial. The initial transfer of fluid from the reservoir/containerthrough the hollow puncture needles immediately after puncture resultsfrom a combination of hydrostatic pressure, fitment retention/reservoirvolume, and the fluid reaction force from initial puncture which drivesthe fluid through the capillary tubes defined by the hollow needles andchannels in the capillary/puncture plate.

Once the fluid passes through the capillary tubes, surface tensioneffects dominate the rise of the fluid against gravity. As the fluidrises, it removes air from the system by pushing it out of the front ofthe ejector openings or holes. Capillary rise holes 2301 are placed onthe ejector plate 2320 of the ejector mechanism above the piezoelectricelement 2322 that serves as a pressure relief for the air in the system.In the absence of these capillary rise holes 2302, the system would beclosed in the region above the ejector openings and the fluid wouldcease to rise due to the increasing build up in air pressure thateventually equalizes with the capillary pressure. In order to achievecomplete rise, all of the air needs to be pushed out of the system. Thecapillary rise holes 2302 (shown from the back in FIG. 25A and from thefront in FIG. 25B) act as pressure equalizing holes and are placed andproperly sized (to prevent fluid leaking) and allow the fluid to risecompletely thereby ensuring that no (or very little) air remains in thesystem. The assembled ejector assembly is shown from the front in FIG.24A and from the rear in FIG. 24B.

FIG. 26 illustrates a schematic outlining fluid flow through thepuncture plate system after complete puncture through the siliconegasket. The liquid flows through the puncture system and up thecapillary plate chamber 2600, pushing air out of the ejector openings orholes 2602 and capillary rise holes 2302. With reference to FIGS. 23 Cand D, the puncture/capillary plate 2304 illustrates a design with 6needles with an inner diameter (ID) of 650 microns and an outer diameter(OD) of 1 mm. The number of needles can be as small as 1 needle but canalso include more needles, e.g., 8 needles with ID dimensions rangingfrom 500 microns-3 mm and OD dimensions ranging from 600 microns-4 mm.The rise holes shown in FIG. 25 can also vary from what is displayed inthis figure. This Fig. shows 5 20 micron diameter sized rise holeshowever the number of holes can be as low as 1 hole but can also includemore holes e.g., 8 holes with the diameter of the holes ranging from 10microns-50 microns.

Alternatively, with reference to FIGS. 44-46, the puncture plate may bedesigned with an elongate needle puncture system. Such designs may, forinstance, be used in connection with certain configurations of reservoirdesigns such as standing rectangular Low Tensile Stress (LTS) reservoirs(i.e., IV bag designs).

The puncture plate may be constructed from any suitable material, suchas described and illustrated herein. By way of non-limiting example, thepuncture plate may be constructed from: Liquid crystal polymer “LCP”(glass filled 0-30%); Nylon 6; Nylon 6,6; Polycarbonate; Polyetherimide(Ultem); Polyether ether ketone (PEEK); Kapton; Polyimide (Kapton);Stainless Steel 316L; Diamond-like carbon (DLC) coated Stainless Steel(300 series); Diamond-like carbon (DLC) coated aluminum; Diamond-likecarbon (DLC) coated copper; Diamond-like carbon (DLC) coatednano-crystalline cobalt phosphate; Nano crystalline cobalt phosphate(nCoP); Gold coated Stainless Steel (300 series); Polymer coated(Polymers listed above) Stainless Steel (300 series); Polymer coated(Polymers listed above) Copper (300 series); Polymer coated (Polymerslisted above) aluminum (300 series), etc.

Although the foregoing describes various embodiments by way ofillustration and example, the skilled artisan will appreciate thatvarious changes and modifications may be practiced within the spirit andscope of the present application. Even though the term “capillary plate”and “puncture plate” is used to describe various embodiments, it will beappreciated that the description is applicable to any fluid loadingplate, need not take the form of a plate and can have any configurationsuitable for channeling the liquid from the reservoir to the ejectormechanism.

As used herein, a reservoir may be any object suitable for holding afluid. By way of example, the reservoir may be made of any suitablematerial capable of containing a fluid. Reservoirs of the presentdisclosure may be rigid or flexible and the reservoirs of the presentdisclosure may further be collapsible. As used herein, collapsiblerefers to a decrease in volume obtainable in a reservoir achieved bysqueezing, folding, crushing, compressing, vacuuming, or othermanipulation, such that total volume enclosed after collapsing is lessthan a volume that could be enclosed in a non-collapsed container. Areservoir may be made of any suitable material that can formed into avolume capable of holding a volume of fluid. Suitable materials, forexample, may either be flexible or rigid and may be formable orpre-formed. As used herein a reservoir, by way of example, may be formedfrom a film.

Furthermore the reservoir may be in fluid communication with a fluidloading plate to form a fluid reservoir interface, and in certainembodiments the fluid loading plate may optionally include a reservoirmating surface or ring to facilitate connection with various fluidreservoir configurations.

In some aspects, the reservoir of the system of the disclosure may beconfigured as a low tensile stress or “LTS” reservoir. An LTS reservoirof the disclosure is generally designed to minimize or eliminatepositive pressure gradients imposed on the system by the reservoircreated from memory effects, crease formation, and unbiased collapse.Such gradients may result in a restoration of the reservoir (expansionin volume) that exerts a net pressure differential on the system,resulting in potential failure by drawing air into the system throughthe ejector openings. In certain aspects, to correct for the pressuredifferential, the LTS reservoir is configured so as to be biased tocollapse into its low lying rest position, which reduces or eliminatesthe possibility of crease formation.

The LTS reservoir is also constructed from thin, flexible (low tensilestress) materials that resists volume expanding, rebounding, and memoryeffects without compromising the inertness and evaporation resistance(see Table 7). LTS reservoirs, as explained above and in further detailbelow, may be constructed in any suitable manner, e.g., includingRF-welding, blow-fill seal processes, form-fill seal processing, etc.

Without intending to be limited by theory, to aid in fluid transportfrom the fluid retention/reservoir and through the capillary tubesduring operation, the LTS reservoir may also be geometrically designedto accelerate the fluid by incorporating the principle of continuity andthe Venturi effect as shown in FIG. 27 and as described below in theBernoulli equation for incompressible flows, and shown in FIG. 28.

Again, without intending to be limited by theory, FIG. 28 describes howaltering the reservoir geometry to a convergent shape profile (largerarea to smaller area) results in the fluid accelerating as it moves downthe reservoir due to the increase in velocity resulting from thecontinuity principle. According to the Bernoulli equation, an increasein velocity from the continuity principle will result in a decrease inpressure in the region of increased velocity (in order to maintaincontinuity). This change in pressure creates a gradient that aids intransporting the fluid into the fitment and through the punctureneedles/capillary tubes. This increase in velocity resulting from aconverging area change is known as the Venturi effect.

FIG. 29 illustrates how hydrostatic pressure drives fluid from the LTSampoule into the fitment and through the puncture needles into the fluidreservoir. To maximize hydrostatic pressure the ampoule needs to beoriented in the upright position since hydrostatic pressure is afunction of height.

TABLE 7 Ampoule Type Ampoule Material Thicknesses RF-Welded Polyurethane(PU), 2-12 mils PU/Polyvinylidene Chloride (PVDC)/PU, Ethylene-VinylAcetate (EVA) Thermal Plastic Polyurethane (TPU) PU/Ethylene-VinylAlcohol (EVOH)/PU Isoplast ® ETPU Blow fill seal Low-DensityPolyethylene 2-15 mils (LDPE) LDPE w/ EVA (10%-50%) EVA (100%) Form fillseal Victrex (LDPE w/ oxygen 2-12 mils barrier layer) TPU

FIG. 30 shows schematic representations of non-fluid accelerating LTSreservoir geometries, which collapse into themselves. The standingrectangle represents a reservoir (similar to an IV bag) that is designedto collapse along its minimum dimension (not shown). The standingrectangle reservoir design is oriented upright to maximize the heightsuch that the effect of hydrostatic pressure is maximized. The secondimage shown is the lying rectangle which functions in a similar way tothe standing rectangle, but without maximizing the effect of hydrostaticpressure. The third image shows a square reservoir configuration. FIG.31 shows schematic representations of fluid accelerating LTS reservoirgeometries.

With reference to FIG. 32, two examples of a circular fluid acceleratingLTS reservoir are illustrated, one constructed by blow-fill-sealprocesses (FIG. 32A) and the other by RF-welding (FIG. 32B). As shown,the amount of collapse may be enhanced when the reservoir is biased tocollapse along the minimum dimension, which in FIG. 32 is the thickness.This type of collapse largely prevents the formation of creases in thereservoir during operation. For standing reservoir designs, furtherprotection against crease formation during operation of an ejectordevice may be created by enclosing the reservoir in a housing thatprevents it from folding over itself as it is emptying. Supporting dataof the performance of these reservoirs is provided herein.

FIG. 33 shows a configuration of a puncture plate 3300 and ablow-fill-seal reservoir with the fitment removed. In certainembodiments, where for self-sealing reservoir materials are used, thepuncture can occur directly through the lower region of the reservoir.The fill compartment shown at the bottom of FIG. 33 is designed to allowfor maximal fluid fill of the secondary reservoir. Alternative puncturemechanisms for the blow fill seal puncture plate assembly are shown inFIG. 34.

FIG. 34 A shows a side profile of another embodiment of the blow fillseal reservoir puncture plate assembly. FIG. 34A shows a stiffeningmechanism in the form of a plastic shell 3400 used to aid in needlepuncture through the blow fill reservoir when it is constructed from aself-sealing material. The figure to the right (FIG. 34B) shows theconfiguration when the blow fill seal reservoir does not self-seal uponpuncture and must be connected to the fitment in the same manner as inFIGS. 22 and 23. As is shown in FIG. 34B, the needles need to passthrough the silicon gasket into the region shown as “Needles puncturethrough here”.

In yet other embodiments of the disclosure, FIG. 35 illustratesgeometries of reservoirs that are biased to collapse a certain way toprevent crease formation. Spray down and pull down procedures andresults for these ampoules are disclosed in the example below.

Example 3: Measurement of Spray Down and Pull Down

Static pull down tests were performed to determine the amount ofnegative pressure that different reservoir configurations, e.g., asshown in FIGS. 30-35, exert on the system as they are removing fluid.The experimental setup for this test is shown in FIGS. 36-37. Theexperimental procedure is as follows: a reservoir is attached to a watercolumn tube that is connected to a vacuum regulator connected to amechanical pump used to draw fluid from the reservoir or ampoule.

Mass deposition testing was performed to determine the mass of a sprayfrom a device at a given frequency or multiple frequencies (massdeposition sweep). Given that some frequencies have a very low mass perspray, which may be at the lower tolerance of the scale used formeasuring the mass, the number of sprays were varied per sample at eachfrequency, then averaged to determine a per spray volume at eachfrequency. This also helped eliminate some error in the measurement.(The scale used could read to the tenth of a milligram.) These setupswere run by a laptop computer, which communicated with the scale, afunction generator, and an oscilloscope. The mass of the sprays wasrecorded as well as the electrical characteristics (phase and magnitudeof the voltage and the current, and the impedance) during the spray. Thesetup was controlled by a labview program that was compiled into alabview executable program and run from the laptop. This program allowedthe user to select the lab equipment in the setup, the com port for thescale, and Universal Serial Bus (USB) identification for theoscilloscope and function generator. The user also defined the testingparameters: voltage, wave form, start frequency, end frequency, stepsize, number of sprays, time between sprays, and spray duration. Theprogram communicated with function generator, setting the frequency forthe spray and the number of cycles to achieve the appropriate sprayduration, and set the oscilloscope to single acquisition from a trigger(Voltage Probe). The program then instructed the function generator totrigger the wave form. The signal was sent to an operational amplifierto boost the signal to the appropriate voltage, which was then appliedto the device (0 to ±90V). At the device, voltage and current probeswere attached to verify the voltage and to read the current. A delay waswritten into the program to allow time for the scale to balance out (≈8sec) before reading the mass from the scale and determine the mass perspray. The scale was zeroed at the start of the test and at every halfgram. At every half gram when zeroing the scale, the scale was cleanedand the reservoir attached to the device was refilled. This insured thatthe device did not run out of fluid, and lowered the error fromevaporation of the fluid on the scale by limiting the amount of fluid onthe scale that could evaporate to 0.5 g. The scale was read after eachset of sprays as defined by the user (normally 5). The mass of thesprays was determined by subtracting the previous value from the currentscale reading, thereby eliminating the time required to zero the scalebetween sets of sprays.

FIG. 38 shows spray down performance (24% of the fluid) of a controlreservoir that is fairly rigid and collapses to form many creases thatresult in a buildup of negative pressure. FIG. 39 shows the results fora representative LTS reservoir of the disclosure, as illustrated in FIG.35. This shows an improvement in spray down performance when creating ageometry biased to collapse in a controlled direction as well aschoosing flexible materials and the appropriate material thickness. Thegraph shows that the majority of the samples (multiple tests of the sameampoule type with the same thicknesses) allowed 80 percent or more ofthe fluid to be removed, with a few outliers, which removed much lessbut better than the creased, control reservoir of FIG. 38.

FIG. 40 shows the spray down performance of two separate runs with oneembodiment of a round LTS reservoir. This reservoir showed a markedimprovement, with over 90 percent of the fluid removed. FIG. 41 showsthe pull downs for select round LTS ampoule designs from FIG. 35. Thesegraphs show a large improvement in the negative pressure generated fromthe system when using the round LTS reservoir. Without intending to belimited by theory, FIG. 42 shows the mechanism involved in invertedspray using a round LTS reservoir, while FIG. 43 shows the actual spraydown performance results of an LTS reservoir sprayed down in a completepuncture system upside down.

In accordance with other aspects of the disclosure, the fluid loadingplate may be designed with a different needle puncture systems, asillustrated in FIGS. 44-46. Such designs may be used in connection withreservoir designs, e.g., standing rectangular LTS reservoirs (i.e., IVbag style designs).

As discussed above, an ejector plate of the system may include capillaryrise holes to provide additional air pressure relief above the activearea (ejector openings). This additional air pressure relief may therebyallow for complete capillary rise of the fluid, which allows theretention/reservoir to be completely filled with fluid. In accordancewith certain aspects of the invention, it was unexpectedly found that ifthese holes are not placed above the ejector openings, the device maynot operate efficiently once the fluid falls below the level of theejector openings (thereby potentially allowing outside air to move intothe system during operation).

When constructing capillary rise holes, optimization of hole size is ofimportance. The holes are preferably large enough to allow a reasonableventing rate so that the capillary rise is not too slow, and arepreferably small enough so that the fluid does not readily leak when thehole is aligned in the direction of gravity. Leaking of the fluid out ofthe rise hole is a function of the size of the hole as well as thesurface tension of the fluid. Fluids with higher surface tensions haveincreased resistance to leaking due to the strength of the fluidmeniscus (which is a function of the surface tension of the fluid)formed within the rise hole by the fluid, which creates a barrier fromfluid leaking out and air moving in. The barrier is breached when thehydrostatic pressure of the reservoir (ampoule) overcomes the surfacetension within the rise hole cavity (see FIG. 47).

The fluid loading plate of the disclosure utilizes capillary action totransport fluid to a location behind the active area of thepiezoelectric mesh for ejection, e.g., as discussed earlier with respectto FIG. 27. Capillary rise is a function of the surface tension of thefluid, surface energy of the surfaces in contact with the fluid (contactangle), and the separation distance of the surfaces in contact with thefluid. To achieve optimal performance for the puncture plate system ahydrophilic material (contact angle between the fluid and the surfaceless than 90 degrees) is preferably used for the capillary channels. Inaddition the material is preferably biocompatible and chemically inert.The separation distance of the surfaces containing the fluid rise arepreferably tuned to ensure that the capillary width is considerably lessthan the capillary length of the fluid thereby ensuring that the surfaceforces are more significant than that of gravity. As shown in FIG. 27,capillary rise in the system occurs between the puncture plate(capillary plate+needles) and the ejector plate (which includes theactive area or openings (piezoelectric mesh screen).

Example 4: Measurement of Capillary Rise

FIGS. 48-49 illustrate capillary pressure for various sized halfdroplets of water and an exemplary ocular medication, latanaprost. Thus,the fluid loading plate separation distance from the ejector plate is animportant parameter for optimization of capillary rise to a certainheight above the ejector openings. This plate separation distance (alongwith viscosity and surface tension of the fluid) also impacts the timefor the fluid to rise to the final height. As shown in FIG. 50, a devicedesigned to spray water and saline can operate with a capillary distanceless than or equal to 2.7 mm. However, the systems of the disclosure arenot so limited, and a capillary distance (separation between capillaryplate and the ejector plate) from 2.7 mm-1.7 mm, and below 1.7 mm may beutilized to achieve greater capillary rise. In certain embodiments, adistance for the puncture plate system may be between 50-200micrometers.

In this regard, FIG. 51 shows capillary rise for saline in capillarychannels made of different materials. FIG. 52 shows capillary risebetween capillary plate and puncture plate without a capillary rise hole2302. This is contrasted with the much better capillary rise shown inFIG. 53, which shows the rise when a capillary rise hole is included.

Further, Tables 8-10 below show capillary rise data in the capillarychannel between the fluid loading plate and the rear surface of theejector mechanism as a result of using different numbers and sizes ofcapillary rise holes 2302. Table 8 shows the data for rise time forwater, Table 9 shows rise time for Latanaprost at room temperature, andTable 10 shows the rise time for Latanaprost refrigerated to 38° F. Someresults had to be discarded as in operative (In-Op, No Fill Past ActiveArea, blank entry) due to defects in the capillary rise holes, or showedasymmetric fill (marked with an asterisk), but the results indicated thebenefits in rise time when using 5 capillary holes, and showed fasterrise times with increase capillary hole size.

TABLE 8 1 Hole 3 Holes 5 Holes  5 um Test 1 395 s 200 s  In-Op Test 2370 s 155 s* In-Op 10 um Test 1 No Fill Past Active 70 s 23 s Area Test2 No Fill Past Active 54 s 25 s Area 20 um Test 1  22 s  8 s  6 s Test 2 22 s 10 s 5.5 s   5 um Test 1  3 s  2 s In-Op Test 2  3.5 s 1.6 s In-Op

TABLE 9 1 Hole 3 Holes 5 Holes 10 um Test 1 No Fill past 60 s 26 s A.A.Test 2  68 s* 32 s 20 um Test 1 11 s  8 s  6 s Test 2  8 s 11 s  5 s

TABLE 10 1 Hole 3 Holes 5 Holes 10 um Test 1 25 s 28 s* Test 2 42 s 44s* 20 um Test 1  7 s 10 s 3.5 s   Test 2 10 s  7 s 4.5 s  

Example 5: Fluid Leak Testing for Select Ocular Drugs and Rise HoleSizes

To test for fluid leaking out of capillary rise holes or vent holes ofone embodiment of the device, a hydrostatic pressure test assembly wasconstructed as shown in FIG. 54. The ejector plate with the rise holesand the ejector assembly was placed beneath the fluid column defined bythe tube. The test fluid was filled into the tube oriented directlyabove the ejector plate with the height of the fluid column carefullymonitored. When the fluid reached test heights (hydrostatic pressure) atwhich the fluid above the ejector openings caused leakage through therise holes and the ejector openings, the heights (corresponding to thepressure values) were recorded and used as a design parameter foroptimizing rise hole dimensions. Results are shown in Tables 5-7 below.

TABLE 11 Water column to side of mesh Water column directly above meshVent Holes Mesh Holes Vent Holes Mesh Holes (inches water) (incheswater) (inches water) (inches water) Annulus Vent Mounting StandardStandard Standard Standard Hole Condition Average Deviation AverageDeviation Average Deviation Average Deviation  1 × 5 um 1 32 31 2 22 329 4 2 28 3 31 23 3 31  3 × 5 um 1 28 27 2 2 26 3 29 3  5 × 5 um 1 Noleak 27 6 2 No leak 28 6 1 × 10 um 1 23 10 27 3 15 1 25 4 2 22 4 27 2 182 23 5 3 × 10 um 1 15 1 25 4 2 14 2 26 5 13 3 23 5 3 × 20 um 1 2 22 2 235 1 × 50 um 1 2 12 4 No leak 3 × 50 um 1 2 14 3 No leak 5 × 50 um 1 2 134 No leak

TABLE 12 Tropicamide column to side of mesh Tropicamide column directlyabove mesh Vent Holes Mesh Holes Vent Holes Mesh Holes (inches (inches(inches (inches Tropicamide) Tropicamide) Tropicamide) Tropicamide)Annulus Vent Mounting Standard Standard Standard Standard Hole ConditionAverage Deviation Average Deviation Average Deviation Average Deviation 1 × 5 um 1 2 7 1.5 6.8 1 1 × 10 um 1 2 4.8 0.9 6 0.7 7 5.6 1.2 3 × 10um 1 2 n/a 6.3 1.3 n/a 4.8 0.5 3 × 20 um 1 2 n/a 8.1 1.6 n/a 3.8 0.8 1 ×50 um 1 2 4 0.9 6 1.3 3 × 50 um 1 2 4.8 0.7 6.4 0.8

TABLE 13 Latanoprost column to side of mesh Vent Holes Mesh Holes(inches Latanoprost) (inches Latanoprost) Annulus Mounting StandardStandard Vent Hole Condition Average Deviation Average Deviation  1 × 5um 1 2 n/a 3.7 0.6 1 × 10 um 1 2 n/a 3.5 0.6 1 × 50 um 1 2 3.3 0.7 3.70.6

Although the foregoing describes various embodiments by way ofillustration and example, the skilled artisan will appreciate thatvarious changes and modifications may be practiced within the spirit andscope of the present application.

As mentioned above, droplets may be formed by an ejector mechanism fromfluid contained in a reservoir that is coupled to the ejector mechanism.The ejector mechanism and reservoir, which together form an ejectorassembly, may be configured to be removable to allow the assembly to bedisposed of or reused. Thus the components may be packaged in a housing,e.g., the upper section 200 of the housing 202 shown in FIG. 2, in aremovable manner. The housing itself may therefore be disposable, or maybe reusable by being configured to receive a removable ejectormechanism. The housing may be handheld, miniaturized, or formed tocouple to a base, and may be adapted for communication with otherdevices. Housings may be color-coded or configured for easyidentification.

While specific embodiments of the ejector mechanism are discussed below,this does not limit the configuration or use of the ejector mechanismnor the features that may be added to the ejector device. Ejectordevices, in some implementations, may include illumination means,alignment means, temperature control means, diagnostic means, or otherfeatures. Other implementations may be part of a larger network ofinterconnected and interacting devices used for subject care andtreatment. The ejector mechanism may, for example, be a piezoelectricactuator as described herein.

Referring to FIGS. 55 A-C, an ejector assembly 5500 may include anejector mechanism 5501 and a reservoir 5520. The ejector mechanism 5501may include an ejector plate 5502 coupled to a generator plate 5532 thatincludes one or more openings or holes 5526. The ejector plate 5502 andgenerator plate 5532 that can be activated by a piezoelectric actuator5504 which vibrates to deliver a fluid 5510, contained in the reservoir5520, in the form of ejected droplets 5512 along a direction 5514.Again, the fluid may be an ophthalmic fluid that is ejected towards aneye 5516 of a human adult, child, or animal. Additionally, the fluid maycontain an active pharmaceutical to treat a discomfort, condition, ordisease of a human or an animal. In some implementations, the generatorplate is a high modulus polymer generator plate, e.g., formed from amaterial selected from the group consisting of: ultrahigh molecularweight polyethylene (UHMWPE), polyimide, polyether ether ketone (PEEK),polyvinylidene fluoride (PVDF), and polyetherimide. comprises a highmodulus polymeric generator plate.

As shown in FIG. 55A, ejector plate 5502 is disposed over the front ofthe reservoir 5520 which contains fluid 5510. The rear surface 5525 ofejector plate 5502 is arranged to be adjacent to the fluid 5510. In thisembodiment, the reservoir 5520 therefore has an open end 5538 which isattached adjacent to surface 5525 and to openings 5526. In thisembodiment, surface 5525 encloses the fluid 5510 in the reservoir 5520.The reservoir 5520 may be coupled to the ejector plate 5502 at aperipheral region 5546 of the surface 5525 of the ejector plate 5502using a suitable seal or coupling. By way of example, the reservoir 5520may be coupled via an O-ring 5548 a. Although not shown, more than oneO-ring can be used. As known in the art, the O-rings may have anysuitable cross-sectional shape. Furthermore, other couplers such aspolymeric, ceramic, or metallic seals can be used. Alternatively, thecoupling can be eliminated altogether and reservoir 5520 may beintegrally connected to ejector plate 5502, for example by welding orover molding. In such an implementation, an opening through which fluidis supplied to reservoir 5520 may be provided (not shown). Inembodiments where couplings are used, the couplings may be maderemovable, e.g., by providing a hinged connection between the reservoir5520 and the ejector plate 5502, or by providing a flexible or non-rigidconnector, e.g., polymeric connector.

The reservoir 5520 may define a peripheral lip or wall 5550 coveringportions of the ejector plate 5502. In the implementation of FIG. 55A,the wall 5550 does not directly contact the ejector plate 5502, ratherit is coupled to O-rings 5548 a. Alternatively, the wall 5550 can bedirectly attached to ejector plate 5502. Instead, the reservoir can bedirectly attached to the ejector plate 5502 and the wall 5550 can beomitted altogether.

The configuration of the reservoir, including the shape and dimension,can be selected based on the amount of fluid 5510 to be stored, as wellas the geometry of the ejector plate 5502. Alternative forms ofreservoirs include gravity-fed, wicking, or collapsible bladders (asdiscussed above and which accommodate pressure differentials). Thesereservoirs may be prefilled, filled using a micro-pump or may beconfigured to receive a replaceable cartridge. The micro pump may fillthe reservoir by pumping fluid into or out of a collapsible ornon-collapsible container. The cartridge may include a container whichis loaded into the reservoir. Alternatively, the cartridge itself may becoupled to a disposable ejector assembly which is then replaced after aspecified number of discharges. Examples of reservoirs are illustratedin U.S. patent application Ser. No. 13/184,484, filed Jul. 15, 2011, thecontents of which are herein incorporated by reference.

In some implementations, the reservoir 5520 includes through holes 5542(only one shown in FIG. 55A) to allow air to escape from or enter thereservoir 5520 and keep the fluid 5510 in the reservoir at theappropriate ambient pressure. The through holes 5542 have a smalldiameter so that the fluid 5510 does not leak from the holes.Alternatively, no openings may be formed in the reservoir 5520, and atleast a portion, e.g., the portion 5544, or the entire reservoir 5520can be collapsible, e.g., in the form of a bladder, as is discussed ingreater detail above. Thus the entire reservoir may, in someembodiments, be made in the form of a flexible or collapsible bladder.Accordingly, as the fluid 5510 is ejected through the openings 5526, thereservoir 5520 changes its shape and volume to follow the changes in theamount of fluid 5510 in the reservoir 5520.

In the embodiment of FIG. 55A, the ejector mechanism 5501 is activatedby being vibrated by a piezoelectric actuator 5504, which in thisembodiment has an annular shape. Two electrodes 5506 a and 5506 b areformed on two opposite surfaces 5536 and 5534 of the piezoelectricactuator 5504 that are parallel to the surface 5522 of the ejector plate5502 and activate the piezoelectric actuator 5504 to vibrate the ejectorplate 5502 and a generator plate 5532. For ease of representation theejector plate 5502 and generator plate 5532 are shown lying in a commonplane. However, as is discussed in greater detail below with respect toFIGS. 1B-1D, the generator plate 5532 in this embodiment is attached toa surface of the ejector plate 5502. The electrodes 5506 a and 5506 bcan be attached to the ejector plate or piezoelectric actuator in anyknown manner including fixing by adhesive or otherwise bonding. They mayalso be overmolded in place to ejector plate 5502. Wires or otherconductive connectors can be used to affect necessary electrical contactbetween the ejector plate 5502 and the electrodes 5506 a and 5506 b.Alternatively, the electrodes may be formed on the ejector plate 5502 byplating or otherwise depositing. By way of example, the electrodes areattached by means of electrically conductive adhesive 5528 which isapplied between the electrode 5506 a and the ejector plate 5502 to placethe electrode 5506 a in electrical contact with the ejector plate 5502.When a voltage is applied across the electrodes 5506 a and 5506 b, thepiezoelectric actuator 5504 deflects ejector plate 5502 and likewisegenerator plate 5532 to change the shape to a more concave or convexshape.

Accordingly, when a voltage is applied across the electrodes 5506 a and5506 b, the piezoelectric actuator 5504 deflects ejector plate 5502 andlikewise generator plate 5532 to change shape to be alternately moreconcave or convex at the resonance frequency of the coupled ejectorplate 5502 and generator plate 5532. The coupled ejector plate 5502 andgenerator plate 5532 deflected by the piezoelectric actuator 5504 at theresonant frequency may amplify the displacement of the coupled ejectorplate 5502 and generator plate 5532 thereby decreasing the powerrequirements of the piezoelectric actuator input. In a further aspect,the damping factor of the resonance system of the coupled ejector plate5502 and generator plate 5532 due to the inherent internal resistance ofthe annulus/mesh limits the movement to prevent a runaway condition andprevent catastrophic failure.

An extensive range of voltages corresponding to different piezoelectricmaterials are known in the art, but by way of example, a voltagedifferential of between 5 and 60 V, or 30 and 60 V, e.g., 40 or 60 V maybe applied to the electrodes. When the direction of the voltagedifferential is reversed, for example to −40 or −60, the plate willdeflect in the opposite direction. In this way, the piezoelectricactuator 5504 causes oscillation of ejector plate 5502 and generatorplate 5532 which constitutes the vibration that results in formation ofthe droplets 5512 from fluid 5510. As the alternating voltage is appliedto electrodes 5506 a and 5506 b, the ejector plate 5502 and thegenerator plate 5532 oscillate, causing the fluid droplets 5512 toaccumulate in the openings 5526 and eventually to be ejected from theopenings 5526 along the direction 5514 away from the reservoir 5520. Thefrequency and wavelength of oscillation may depend on many factors,including but not limited to, the thickness, composition and morphologyand mechanical properties of the ejector plate 5502, including itsstiffness, the properties of the generator plate 5532, the volume of theopenings 5526, the number of openings 5526, composition and structure ofthe piezoelectric actuator 5504, piezoelectric actuation drivingvoltage, frequency and waveform, the viscosity of the fluid, temperatureand other factors. These parameters may be adjusted or selected tocreate the desired droplet stream. The frequency of droplet ejectionalso depends on many factors. In some implementations, the droplets 5512are ejected at a frequency lower than the pulse frequency applied to thepiezoelectric actuator 5504. For example, the droplets 5512 are ejectedevery 1-1000 cycles, and more specifically 8-12 cycles, of the ejectorplate/generator plate vibration (which vibrate at the same frequency asthe actuator 5504). In some implementations, the generator platecomprises a high modulus polymeric generator plate.

In one embodiment of the present disclosure, as illustrated in FIG. 55C, the ejector plate 5502 may be centro-symmetrically mounted bysymmetric mounting structures 5555 through optional mounting holes 5551.Symmetric mounting structures may maximize the constant velocity surfacearea of ejector plate 5502, suppress anti-symmetric modes andmechanically match the piezoelectric material to the low order Besselmodes. In this embodiment there are four mounting tabs 5555 as shown inFIG. 1C. In another embodiment, there may be eight mounting tabs 5555.In yet another embodiment, there may be 16 mounting tabs 5555.

In certain aspects, the centro-symmetrical mounting provides for the useof piezoelectric materials that are lead free, e.g., BaTiO₃. In oneembodiment of the disclosure, the resonance coupling of the ejectorplate 5502 to a generator plate 5532 and to the piezoelectric actuator5504 provides for the use of piezoelectric materials having smallerdisplacements than industry standard piezoelectric materials.

In accordance with certain embodiments of the disclosure, with referenceto FIG. 55A, an ejector plate 5502 may be a simple ejector plate 5502having an integrated generator plate 5532 having a center region 5530and openings 5526. In other embodiments of the disclosure (FIGS. 55B-D)the ejector plate 1602 may be hybrid ejector plate 1602 having a coupledgenerator plate 5532 having a center region 5530 and openings 5526. Thefirst surface 5522 of the ejector plate 5502 may be coupled to thegenerator plate 5532. The ejector plate 5502 may generally comprise acentral open region 5552 configured to align with the generator plate5532. The generator plate 5532 may then be coupled with the ejectorplate 5502 such that a center region 5530 of the generator plate 5532aligns with the central open region 5552 of the ejector plate 5502. Thecenter region 5530 of the generator plate 5532 may generally include oneor more openings or holes 5526, and alignment of the central open region5552 of the ejector plate 5502 with the central region 5530 of thegenerator plate 5532 with its one or more openings 5526 allows forthrough communication of the one or more openings 5526. In someembodiments, the generator plate comprises a high modulus polymericgenerator plate.

In certain embodiments, the central open region 5552 of the ejectorplate 5502 may be smaller than the generator plate 5532 to providesufficient overlap of material so as to allow for coupling of theejector plate 5502 and the generator plate 5532. However, the centralopen region 5552 of the ejector plate 5502 should, in such embodiments,be sized and shaped so as to not interfere with or obstruct the centerregion 5530 (and thereby one or more openings 5526) of the generatorplate 5532. By way of non-limiting example, the central open region 5552of the ejector plate may be shaped in a manner similar to the generatorplate 5532, and may be sized so as to have, for example, about 0.5 mm toabout 4 mm, e.g., about 1 mm to about 4 mm, or about 1 mm to about 2 mm,etc., of overlap material available for coupling of the generator plate5532 to the ejector plate 5502 (e.g., overlap on all sides). Forinstance, the central open region 5552 of the ejector plate may beshaped as a square, a rectangle, a circle, an oval, etc., in a manner togenerally match the shape of the generator plate 5532, and sized suchthat the central open region 5552 is, for example, about 0.5 mm to about4 mm smaller in overall dimensions (i.e., the diameter of a circle isabout 0.5 to about 4 mm smaller, the major and minor axes of an oval areabout 0.5 to about 4 mm smaller, the length of the sides of a square orrectangle are about 0.5 to about 4 mm smaller, etc.). In someembodiments, the generator plate comprises a high modulus polymericgenerator plate.

Except as otherwise described herein, exemplary ejector mechanisms aredisclosed in U.S. application Ser. No. 13/712,784, filed Dec. 12, 2012,entitled “Ejector Mechanisms, Devices, and Methods of Use”, and Ser. No.13/712,857, filed Dec. 12, 2012, entitled “High Modulus PolymericEjector Mechanism, Ejector Device, and Methods of Use,” the contents ofwhich are herein incorporated by reference in their entireties.

The generator plate 5532 may be coupled to the ejector plate 5502 usingany suitable manner known in the art, depending on the materials in use.Examples of coupling methods include the use of adhesive and bondingmaterials, e.g., glues, epoxies, bonding agents, and adhesives such asloctite 409 or other suitable super glue, welding and bondingprocessing, e.g., ultrasonic or thermosonic bonding, thermal bonding,diffusion bonding, or press-fit etc.

Surface 5522 of ejector plate 5502 may also be coupled to apiezoelectric actuator 5504, which activates generator plate 5532 toform the droplets upon activation. The manner and location of attachmentof the piezoelectric actuator 5504 to the ejector plate 5502 affects theoperation of the ejector assembly 5500 and the creation of the dropletstream. In the embodiment of FIGS. 55B-C, the piezoelectric actuator5504 may be coupled to a peripheral region of surface 5522 of plate5502, while generator plate 5532 is coupled to surface 5522 so as toalign with the central open region 5552 of ejector plate 5502, asdescribed above. The piezoelectric actuator 5504 is generally coupled tothe ejector plate 5502 so as to not cover or obstruct the central region5530 (and thereby one or more openings 5526) of the generator plate5532. In this manner, fluid 5510 may pass through the openings 5526 toform droplets 5512 (as shown in FIG. 55A).

The structure defined by the ejector plate 5502 and optionally coupledgenerator plate 5532 possesses a large number of eigenmodes whichdefine, for each eigenmode, the shape the structure will take when saidstructure is excited. Examples of eigenmodes are presented in FIG. 3.For maximum ejection at any of these eigenmodes, the piezoelectricactuator 5504 must be shaped properly and placed in a position thatprovides the least amount of resistance to the deformation of theejector plate 5502 and optionally coupled generator plate 5532 in thedesired eigenmode. If the piezoelectric actuator 5504 provides arestriction on the shape of a given eigenmode the stiffness of thepiezoelectric actuator 5504 and bonding layer may damp the mode (provideresistance toward continued movement), and may force the movement of thestructure to be extremely dependent on the piezoelectric actuator 5504material properties. This can limit the mass ejection in approximatelythe ratio of the piezoelectric actuator 5504 properties.

In some implementations, the ejector plate 5502 and optionally coupledgenerator plate 5532 eigenmodes can be excited with low or no resistance(other than the internal the ejector plate 5502 and optionally coupledgenerator plate 5532 resistance) to continued movement (ejector plate5502 and optionally coupled generator plate 5532 resonance) simply bymounting the piezoelectric actuator 5504 to the edge of the ejectorplate 5502 and optionally coupled generator plate 5532. By bonding thepiezoelectric actuator 5504 to the edge of the ejector plate 5502 andoptionally coupled generator plate 5532, the least possible resistanceto ejector plate 5502 and optionally coupled generator plate 5532movement can be provided. In an edge bonded, or near edge bondedembodiment, limitations of the piezoelectric actuator 5504 propertiesare minimized, as the mechanical resistance offered by the stiffness ofthe ceramic (e.g., the piezoelectric actuator 5504) and bonding to theeigenmode shapes is less than that of the ejector plate 5502 andoptionally coupled generator plate 5532 itself.

In certain aspects of the present disclosure, the eigenmodes of theejector plate 5502 and optionally coupled generator plate 5532 may beoptimized by varying the dimensions of the piezoelectric actuator 5504.In an aspect, a given eigenmode may be excited by mounting the drivingforce (e.g., piezoelectric actuator 5504) at the right location,relative to the standing wave on the ejector plate 5502 and optionallycoupled generator plate 5532, and constraining the dimensions of thepiezoelectric actuator 5504—within the standing wave node or anti-node(depending on dominant radial or longitudinal drive mode). Theeigenmodes of a ejector plate 5502 and optionally coupled generatorplate 5532 and their shape can be found by solution of theSturm-Liouville problem analytically.

While idealized eigenmodes of a membrane (e.g., a drum) may be found bysolution of the Sturm-Liouville problem, in certain aspects of thepresent disclosure it becomes mathematically difficult or evenintractable to analytically solve for the eigenmode shapes, frequencies,and corresponding amplitude coefficients of the vibration of an ejectorplate 5502 and optionally coupled generator plate 5532. Analyticallimitations to obtaining a solution to the Sturm-Liouville problem arisewhen an idealized membrane is loaded, includes a driving element, has anon-ideal boundary condition, or comprises multiple materials.

In aspects according to the present disclosure, the ejector plate 5502and optionally coupled generator plate 5532 may include loads such asfluid 5510. In other aspects, the ejector plate 5502 and optionallycoupled generator plate 5532 may include a piezoelectric actuator 5504driving element. In another aspect, the ejector plate 5502 may includethe coupled generator plate 5532 comprising one or more materials. In afurther aspect, the ejector plate 5502 may be of non-uniform thickness.Similarly, in an aspect, the coupled generator plate 5532 may be ofnon-uniform thickness. In yet another aspect, the generator plate 5532may have openings 5526 that are non-uniform and may lead to non-trivialanalytical solutions.

The analytic limitations arising from a non-idealized membrane may beovercome. In certain aspects according to the present disclosure,computational software may be used which divides an entire structureinto smaller discrete elements using Finite Element Methods (FEM). In anaspect, the computational software discretizes the structure intoelements that may be one half or less of the size of the minimumwavelength (maximum frequency) of vibrational interest. In other aspectsthe discrete elements may be one fifth or less of the size of theminimum wavelength (maximum frequency) of vibrational interest. In otheraspects, the discrete elements may be one tenth or less of the size ofthe minimum wavelength (maximum frequency) of vibrational interest. Inanother aspect of the present disclosure, the discrete elements may beone fifteenth or one twentieth or less of the size of the minimumwavelength (maximum frequency) of vibrational interest. In an aspect,the analytical problem comprising a partial differential equation maythen be represented by the central differences at each point of thediscrete elements. In another aspect the partial differential equationmay be solved by finding a sum of basis functions that minimize thesystem energy.

In an aspect, using FEM techniques, the eigenmode frequencies and shapesmay be determined through modal analysis for a given set of boundaryconditions, such as free, simply supported, clamped, pinned, or somehybrid of these boundary conditions. In an aspect, the shape of thepiezoelectric actuator 5504 may be determined by the eigenmode shape itis meant to drive. In certain aspects, the shape of the piezoelectricactuator 5504 is largely determined by the counterbalance of appliedforce per unit area, which is directly related to the area of thepiezoelectric actuator 5504 in contact with the ejector plate 5502 andoptionally coupled generator plate 5532, and the resistance or dampingapplied to the mode shape by the stiffness of the bonded piezoelectricactuator 5504.

In certain embodiments according to the present disclosure, once thepiezoelectric actuator 5504 location and initial size is determined, itis modeled on the ejector plate 5502 and simulated with a voltageapplied to the top of the piezoelectric actuator 5504 and grounded onthe ejector plate 5502 and optionally coupled generator plate 5532terminal. The ejector plate 5502 and optionally coupled generator plate5532 can be a simple ejector plate 5502, a hybrid ejector plate 5502having a coupled generator plate 5532, a simple or hybrid ejector plate5502 having a 4 post structure, electric field screened structure, orany other combination of structures. The piezoelectric actuator 5504excitation frequency is swept in the simulation from near zero frequencyup to several hundred kilohertz (kHz), or more generally any frequency.The mode shape, amplitude of the displacement and velocity the simple orhybrid ejector plate 5502 experiences are computed for each frequency inthe sweep. By applying FEM techniques, the amplitude and velocity of adesign may be assessed.

If the ejector plate 5502/piezoelectric actuator 5504 system moves withadequate amplitude and velocity at the desired frequency the design iscomplete. If not, the design is tuned by thinning or thickening thepiezoelectric actuator 5504 height in order to alter the damping of theejector plate 5502 applied by the piezoelectric actuator 5504. Incertain aspects, the piezoelectric actuator 5504 can also be tuned inlateral/radial thickness in order to reduce the damping of specificmodes or to shift resonant frequencies either higher or lower.Simulations are repeated given the trending of the piezoelectricactuator 5504 sizing until design optimization is complete.

As the ejector assembly 5500 is used for delivering therapeutic agentsor other fluids to the desired target, e.g., the eye, the ejectorassembly 5500 may be designed to prevent the fluid 5510 contained in thereservoir 5520 and the ejected droplets 5512 from being contaminated. Insome implementations, for example, a coating (not shown) may be formedover at least a portion of the exposed surface(s) of the piezoelectricactuator 5504, the ejector plate 5502, the generator plate 5532, etc.,that are exposed to the fluids. The coating may be used to preventdirect contact of the piezoelectric actuator 5504 and the electrodes5506 a and 5506 b with the fluid 5510. The coating may be used toprevent interaction of the ejector plate 5502 or generator plate 5532with the fluid. The coating or a separate coating may also be used toprotect the piezoelectric actuator 5504 and electrodes 5506 a and 5506 bfrom the environment. For example, the coating can be a conformalcoating including a nonreactive material, e.g., polymers includingpolypropylene, nylon, or high density polyethylene (HDPE), gold,platinum, or palladium, or coatings such as Teflon®. Coatings aredescribed in further detail herein.

The generator plate 5532 may be a perforated plate that contains atleast one opening 5526. The one or more openings 5526 allow the dropletsto form as fluid 5510 is passed into the openings and ejected fromgenerator plate 5532. The generator plate 5532 may include any suitableconfiguration of openings. Examples of generator plates 5532 comprisinghigh modulus polymers are illustrated in U.S. application Ser. No.13/712,857, filed Dec. 12, 2012, entitled “High Modulus PolymericEjector Mechanism, Ejector Device, And Methods Of Use”, the contents ofwhich are herein incorporated by reference in its entirety for thepurpose of such disclosures.

In some implementations, the ejector plate 5502 may be formed of ametal, e.g., stainless steel, nickel, cobalt, titanium, iridium,platinum, or palladium or alloys thereof. Alternatively, the plate canbe formed of other suitable material, including other metals orpolymers, and may be coated as described herein. The plate may be acomposite of one or more materials or layers. The plate may befabricated for example by cutting from sheet metal, pre-forming,rolling, casting or otherwise shaping. The coatings may also bedeposited by suitable deposition techniques such as sputtering, vapordeposition including physical vapor deposition (PAD), chemical vapordeposition (COD), or electrostatic powder deposition. The protectivecoating may have a thickness of about less than 0.1 μm to about 500 μm.It is desirable that the coating adhere to the ejector plate 5502sufficiently to prevent delamination when vibrating at a high frequency.

Referring to FIGS. 55B and 55D, in one implementation, the ejector plate5502 and generator plate 5532 may have concentric circular shapes. Incertain embodiments, the ejector plate may be larger than the generatorplate, so as to accommodate coupling of the generator plate and othercomponents (e.g., piezoelectric actuator, etc.) described herein. Incertain embodiments, the overall size or diameter of the generator plate5532 may be, at least in part, determined by the size of central region5530 and by the arrangement of openings 5526. In some embodiments, thegenerator plate comprises a high modulus polymeric generator plate.

However, both plates may independently have other shapes, e.g., an oval,square, rectangular, or generally polygonal shape, and may be the sameor different. Overall size and shape may be any suitable size and shape,and may be selected based on ejector device design parameters, e.g.,size and shape of an outer device housing, etc. Additionally, the platesneed not be flat, and may include a surface curvature making it concaveor convex. The piezoelectric actuator 5504 may be of any suitable shapeor material. For example, the actuator may have a circular, oval,square, rectangular, or a generally polygonal shape. The actuator 5504may conform to the shape of the ejector plate 5502, generator plate5532, or regions 5530 or 5552. Alternatively, the actuator 5504 may havea different shape. Furthermore, the actuator 5504 may be coupled to theejector plate 5502 or surface 5522 of the ejector plate 5502 in one ormore sections. In the example shown in FIGS. 55B-D, the piezoelectricactuator 5504 is in the shape of a ring that is concentric to theejector plate 5502, generator plate 5532, and regions 5530/5552.

In some implementations, the ejector plate 5502 and/or generator plate5532 may be coated with a protective coating that has anti-contaminationand/or anti-microbial properties. The protective coating can beconformal over all surfaces of the ejector plate and/or generator plate,including surfaces defining the openings 5526. In other implementations,the protective coating can be applied over selected surfaces, e.g., thesurfaces 5522, 5525, or surface regions, e.g., parts of such surfaces.The protective coating can be formed of a biocompatible metal, e.g.,gold, iridium, rhodium, platinum, palladium or alloys thereof, or abiocompatible polymer, e.g., polypropylene, HDPE, or Teflon®.Antimicrobial materials include metals such as silver, silver oxide,selenium or polymers such as polyketones. The protective coating can bein direct contact with the fluid 5510 or the droplets 5512. The coatingmay provide an inert barrier around the fluid or may inhibit microbialgrowth and sanitize the fluid 5510 and/or the droplets 5512.

Additionally, one or both of the surface 5522 of ejector plate 5502 andthe wetted surface of generator plate 5532 that faces the reservoir 5520may be coated with a hydrophilic or hydrophobic coating. Additionally,the coating may be coated with a protective layer. The surfaces may alsobe coated with a reflective layer. A coating layer may be bothprotective and reflective. Alternatively, one or more of the surfacesmay have been formed to be reflective. For example, the surfaces may bemade of stainless, nickel-cobalt, or other reflective material. Asurface may have been formed or polished to be reflective. In additionto making the surface reflective, the surface may also be backlit on itssurface or around its perimeter. In ophthalmic applications, areflective surface aids the user in aligning the ejector assembly withthe eye.

If desired, surfaces of the ejector assembly may include coatings thatmay be pre-formed by dipping, plating, including electroplating, orotherwise encapsulating, such as by molding or casting. The coatings mayalso be deposited by suitable deposition techniques such as sputtering,vapor deposition, including physical vapor deposition (PAD) and chemicalvapor deposition (COD), or electrostatic powder deposition. Theprotective coating may have a thickness of less than 0.1 μm to about 500μm. It is desirable that the coating adhere to the plate sufficiently toprevent delamination when vibrating at a high frequency.

Piezoelectric actuator 5504 may be formed from any suitable materialknown in the art. By way of example, in some implementations, thepiezoelectric actuator can be formed from PZT, barium titanate orpolymer-based piezoelectric materials, such as polyvinylidine fluoride.The electrodes 5506 a and 5506 b can be formed of suitable conductorsincluding gold, platinum, or silver. Suitable materials for use as theadhesive 5528 can include, but is not be limited to, adhesives such assilicone adhesives, epoxies, or silver paste. One example of aconductive adhesive includes Thixotropic adhesive such as Dow CorningDA6524 and DA6533. The reservoir 5520 may be formed of a polymermaterial, a few examples of which include Teflon®, rubber,polypropylene, polyethylene, or silicone.

Piezoelectric ceramic materials are isotropic in the unpolarized state,but they become anisotropic in the polarized state. In anisotropicmaterials, both the electric field and electric displacement must berepresented as vectors with three dimensions in a fashion similar to themechanical force vector. This is a direct result of the dependency ofthe ratio of dielectric displacement, D, to electric field, E, upon theorientation of the capacitor plate to the crystal (or poled ceramic)axes. This means that the general equation for electric displacement canbe written as a state variable equation:

D _(i)=∈_(ij) E _(j)

The electric displacement is always parallel to the electric field, thuseach electric displacement vector, D_(i), is equal to the sum of thefield vectors, E_(j), multiplied by their corresponding dielectricconstant, ∈_(ij):

D ₁=∈₁₁ E ₁+∈₁₂ E ₂+∈₁₃ E ₃

D ₂=∈₂₁ E ₁+∈₂₂ E ₂+∈₂₃ E ₃

D ₃=∈₃₁ E ₁+∈₃₂ E ₂+∈₃₃ E ₃

The majority of the dielectric constants for piezoelectric ceramics (asopposed to single crystal piezoelectric materials) are zero. The onlynon-zero terms are:

∈₁₁=∈₂₂,∈₃₃

The piezoelectric effect relates mechanical effects to electricaleffects. These effects are highly dependent upon their orientation tothe poled axis. The axis numbering scheme is shown in FIG. 56. Forexample, for the electro-mechanical constant d_(ab), a=electricaldirection; b=mechanical direction and for electro-mechanical constantD₃₃=∈₃₃ E₃ with mechanical displacement in the poled direction, Z inthis case. Referring to FIG. 55A, the Z direction is the direction ofthe ejected droplets 5512, direction 5514.

Accordingly, D₃₃ is the induced polarization in direction Z (poleddirection, corresponding to direction 5514 in FIG. 55A) which isparallel to the direction in which the ceramic material is polarized.

In accordance with certain embodiments of the disclosure, piezoelectricmaterials may be described by mechanical displacement in the poleddirection, Z (e.g. direction 5514 of FIG. 55A).

In some embodiments, the piezoelectric material may be a lead Zirconiumtitanate (PZT) having a D₃₃=330 pC/N. In an another embodiment, thepiezoelectric material may be a type of a PbTiO3-PbZrO3 (PZT)-basedmulti-component system that is widely used. Commercially available PZTpiezoelectric ceramics include PZT-4 having a D₃₃ of 225 pC/N, PZT-5Ahaving a D₃₃ of 350 pC/N, and PZT-5H having a D₃₃ of 585 pC/N. The(PZT)-based piezoelectric actuator can be formed from a material havinga D₃₃ of greater than 300 pC/N. In another embodiment, the piezoelectricceramic may have a D₃₃ of 200 pC/N to 300 pC/N. In another embodiment,the piezoelectric ceramic may have a D₃₃ of 250 pC/N to 300 pC/N.

In some implementations, it may be desirable to eliminate lead from thepiezoelectric material for safety reasons and FDA/EU compliance. In animplementation, a lead free piezoelectric ceramic may be used having aD₃₃ of less than 300 pC/N. In another embodiment, a lead freepiezoelectric ceramic may have a D₃₃ of less than 200. In yet anotherembodiment, a lead free piezoelectric ceramic may have a D₃₃ of between150 pC/N and 200 pC/N. In yet another embodiment, the D33 of the leadfree ceramic may be less than 150 pC/N. In yet another embodiment, alead free piezoelectric ceramic may have a D₃₃ of between 100 and 150pC/N. In yet another embodiment, the D₃₃ of a lead free ceramic suitablefor a piezoelectric actuator may be less than 100 pC/N.

In some embodiments the piezoelectric device may be prepared fromcommercially available materials. For a non-limiting example, materialsavailable from Sunnytec Powder Materials presented in Table 14 may besuitable for piezoelectric devices of the disclosure.

TABLE 14 Materials Physical & S-42 S-44 S-44-2 S-81 S-51 S-52 S-53 S-54S-55 S101-D S101-F Properties P-42 FM-2-1 SP-12-4 P-8 P-5A FT-3 FT-4P-5H TK-4800 S101-D S101-F Density (g/cm³) p 7.6 7.7 7.7 7.6 7.6 7.567.56 7.6 7.7 7.55 7.6 Curie Tc 305 300 280 320 260 280 250 180 170 185165 temperature (° C.) Dielectric 33 T/0 1450 1550 1600 1030 2300 22003200 3800 4600 3200 4200 constants Dissipation tgo 0.4 0.4 0.5 0.3 1.51.8 1.8 1.7 2 1.6 1.6 factor (%) Coupling K_(p) 65 68 66 58 71 80 81 7781 72 68 Coefficients (%) Kt 48 48 47 46 51 51 52 52 51 50 46 K31 33 3435 30 38 43 44 42 45 38 36 Frequency N_(p) 2230 2250 2220 2300 2080 19601950 1980 1950 2030 2100 constants Nt 2050 2050 2080 2050 2040 2030 20452040 2020 2040 2100 (MHz) NL 1650 1630 1630 1655 1545 1420 1420 15001465 1510 1545 Mechanical Qm 600 1400 1200 1000 80 70 65 65 55 100 70quality factor Piezoelectric d33 320 330 330 250 450 550 640 650 750 620650 Charge d31 −155 −135 −140 −110 −200 −260 −300 −290 −300 −250 −265Constants (×10−12 M/V) Piezoelectric g33 25.8 23.4 23.2 27.4 22.1 28.222.6 19.3 18.4 21.8 17.4 voltage g31 −12.5 −10.5 −10.2 −9.8 −11.1 −11.5−10.8 −8.6 −7.5 −8.5 −7.1 constants (×10−3 Vm/N) Elastic constants SE1111.5 12.5 12.1 12.1 13.8 16.2 16.5 14.1 15.2 14.5 13.7 (×10−12 m2/N)SD11 10.2 11.2 11.1 10.9 11.8 13.3 13.2 11.6 12.9 12.3 11.8

In some embodiments, the piezoelectric material may be a BiFeO₃-basedceramic. In some embodiments, the ceramic may be selected from the groupconsisting of (Bi,Ba)(Fe,Ti)O₃, (K,Na,Li)NbO₃, (K,Na,Li)NbO₃,(K,Na,Li)NbO₃, (K,Na,Li)NbO3, Bi(Fe,Mn)O₃+BaTiO₃, Bi(Fe,Mn)O₃+BaTiO₃,BiFeO₃—NdMnO₃—BiAlO3, (Bi,La)(Fe,Mn)O₃, (Bi,La)(Fe,Mn)O3,BiFeMnO3-BaTiO₃, Bi(Fe,Mn)O3-BaZrTiO₃, (Bi,La)(Fe,Mn)O₃,(Bi,La)(Fe,Mn)O₃, (Bi,Ba)(Fe,Ti)O₃, Bi(Zn,Ti)O₃—La(Zn,Ti)O₃—Ba(Sc,Nb)O₃(d33=250), BiFeO₃, (Ba, M)(Ti,Ni)O₃, BiFeO₃, Bi(Al,Ga)O₃, BT-BiFeO₃,Bi(Fe,Al)O₃, Bi(Fe,Al)O₃, Bi(Fe,Co,Mn)O₃, BiFeO₃—BaTiO₃, BiFeO₃—BaTiO₃,Bi(Al,Ga)O₃ (d33=150), Bi(Al,Ga)O₃, BiFeO₃+AD, BiFeO₃+BaTiO₃,BiFeO₃-based, BaTiO₃—BiFeO₃, (Bi, x)(Fe,Mn)O₃, and (Bi, x)(Fe, Ti,Mn)O₃.

In some embodiments, the piezoelectric material may be a bismuth sodiumtitanate (BNT) material or a bismuth potassium titanate (BKT) material.The BNT or BKT material may be selected from the group consisting of(1-x)Bi_(0.5)Na_(0.5)TiO₃— xLaFeO₃, (1-x)Bi_(0.5)Na_(0.5)TiO₃— xNaSbO₃,(1-x)Bi_(0.5)Na_(0.5)TiO₃— xBiCrO₃, (1-x)Bi_(0.5)Na_(0.5)TiO₃— xBiFeO₃,Bi_(0.5)(Na_(1-x),K_(x))_(0.5)TiO₃ (BNKT),Bi_(0.5)(Na_(1-x)K_(x))_(0.5)TiO₃ (BNKT),Bi_(0.5)(Na_(1-x)K_(x))_(0.5)TiO₃ (BNKT),Bi_(0.5)(Na_(1-x)K_(x))_(0.5)TiO₃ (BNKT), ((1-x)Bi_(1-a)Na_(a))TiO₃—(1-x)LiNbO₃, Bi_(0.5)(Na_(1-x)Lix)_(0.5)TiO₃, Bi_(0.5)(Na,K)_(0.5)[Ti,(Mg, Ta)]O₃, Bi_(0.5)(Na,K)_(0.5)[Ti,(Al, Mo)]O₃,Bi_(0.5)(Na,K)_(0.5)[Ti,(Mg, Nb)]O₃, Bi_(0.5)(Na,K)_(0.5)[Ti,(M,V)]O₃,Bi_(0.5)(Na,K)_(0.5)[Ti,(M,V)]O₃, BNT-BT-KNN, (1-x)Bi_(0.5)Na_(0.5)TiO₃—xBaTiO₃ (BNBT) (d₃₃=100×10⁻¹²C/N or more), BNT-BKT-BT (d₃₃=158pC/N),BNT-BKT-BT+PT (d33=127), BNT-KN, Bi_(0.5)Na_(0.5)TiO₃— BaTiO₃ (BNBT)(d₃₃=253pC/N), NGK2, BNT-BKT-BT, NGK, BNT-BKT-BT, NGK4,Bi_(0.5)Na_(0.5)TiO₃— BaTiO₃—CaTiO₃— Ba(Zn_(1/3)Nb_(2/3))O₃+Y₂O₃, MnO,(1-v)[(Li_(1-y)Na_(y))zNbO₃]-v[Bi_(0.5)Na_(0.5)TiO₃,(1-v-x)[(Li_(1-y)Na_(y))zNbO₃]-xLMnO₃-v[Bi_(0.5)Na_(0.5)TiO₃],Bi_(0.5)Na_(0.5)TiO₃, BNT-BT, BNT-BT, xBi_(0.5)Na_(0.5)TiO₃— y(MNbO₃)—(Z/2)(Bi₂O₃—Sc₂O₃) (M=K, Na), BNT-BKT-Bi(Mg2/3Ta1/3)O3,[(Bi_(0.5)Na_(0.5))xMy]z(TiuNv)O₃ (M=Ba, Mg, Ca, Sr, (Bi_(0.5)K_(0.5)))(N=Zr, Hf), [(Bi_(0.5)Na_(0.5))xMy]z(TiuNv)O₃ (M=Ba, Mg, Ca, Sr,(Bi_(0.5)K_(0.5)), others) (N=Zr, Hf, others), BNT-BKT-BT-CT-NaNbO₃,BNT-BKT-Bi(Ni,Ti)O₃, BNT-BKT-Bi(Ni,Ti)O₃, BNT-BKT-BT, BNT-BT-ST,BNT-BKT-BT, BNT-BKT-AgNbO₃, BNT-BKT-BT, BT-BKT, BNT-BT-Bi(Fe0.5Ti0.5)3,BNT-BKT-Bi(Zn0.5Zr0.5)O3, BNT-BKT-Bi(Fe0.5Ta0.5)O3, BNT-BKT-Bi(M1,M2)O3,BNT-BKT, BNT-BT, BNT-BKT, Bi_(0.5)K_(0.5)TiO₃ (BKT) andBi_(0.5)Na_(0.5)TiO₃— (1-x)ABO₃.

In some implementations, the piezoelectric material may be a dual-modemagnetostrictive/piezoelectric bilayered composite, tungsten-bronzematerial, a sodium niobate material, a barium titanate material, and apolyvinylidine fluoride material. Examples of suitable materials for thepiezoelectric actuator of the disclosure include A2Bi4Ti5O18(A=Sr,Ca,(Bi_(0.5)Na_(0.5)),(Bi_(0.5)Li_(0.5)), ((Al-xBix)2Bi4Ti5O18(A=Sr,Ca,(Bi_(0.5)Na_(0.5)), (,(Bi_(0.5)Li_(0.5)),(Bi_(0.5)Li0.5),Bi4Ti3O12-x{Sr1-aA′a)TiO3 (A=Ba, Bi_(0.5)Na0.5, Bi_(0.5)K0.5,Bi_(0.5)Li0.5), Bi4Ti3O12-(Ba, A)TiO₃, Bi4Ti3O12-x{(Sr1-aA′a)TiO3-ABO3}(A′=Ba, Bi_(0.5)Na0.5, Bi_(0.5)K0.5, Bi0.5Li0.5, A=Bi,Na,K,Li, B=Fe,Nb),(Al-xBix)Bi4Ti4O15 (A=Sr,Ba), BaBi4Ti4O15,(Sr2-aAa)x(Na1-bKb)y(Nb5-cVc)O15 (A=Mg, Ca, Ba) d33=80pC/N or more,Tc=150° C. or more, (Sr2-aAa)x(Na1-bKb)y(Nb5-cVc)O15, (Na0.5Bi_(0.5))1-xMxBi4Ti4O15, Bi4Ti3O12, SrBi2(Nb,W)O9,(Sr1-xM1x)Bi2(Nb1-zWy)2O9, (Sr, Ca)NdBi2Ta2O9+Mn, (Sr1-xMx)(Bi, Nd)(Nb,Ta)2O9, Bi2(Sr1-xMx)Nb2O9 (M=Y, La), (Sr2CaK)Nb5O15 (d33=120).

In implementations according to the disclosure, the niobate material maybe selected from (Sn,K)(Ti,Nb)O3, KNbO3-NaNbO3-LiNbO3-SrTiO3-BiFeO3,KNbO3-NaNbO3-LiNbO3, KNbO3-NaNbO3-LiNbO3, xLiNbO3-yNaNbO3-zBaNb2O6,NaxNbO3-AyBOf (A=K,Na,Li,Bi B=Li,Ti,Nb,Ta,Sb),(1-x)(Na1-aMna)b(Nb1-aTia)O3-xMbTiO3(M=(Bi1/2K1/2),Bi1/2Na1/2),(Bi1/2Li1/2), Ba, Sr,(K,Na,Li)NbO3-Bi(Mg,Nb)O3-Ba(Mg,Nb)O3,(1-x)[(Li1-yNay)zRO3]-xLMnO3(R=Nb,Ta,Sb, L=Y,Er,Ho,Tm, Lu, Yb),(LixNa1-x-yKy)z-2wMa2wNb1-wMbwO3 (Ma=²⁺ metal A, Mb=³⁺ metal B), NN-BTd33=164, K1-xNaxNbO3+ Sc₂O3, [(K1-xNax)1-yAgy]NbO3-z[Ma+][O2-](M=additive), Li(K,Na)(Nb,Sb)O3, KNbO3-NaNbO3 (d33=200),(Li,Na,K)(Nb,Ta,Sb)O3, (K,Na,Li)NbO₃, KNbO3+MeO3 (MnWO3. etc.)(d33=130).

Barium titanate material is an inorganic compound with the chemicalformula BaTiO₃. Barium titanate materials include BaTiO₃ materials thatfurther comprise substoichiometric amounts of other elements. Examplesof other elements that are included in BaTiO₃ materials include rareearth elements and alkaline earth metals. The substoichiometric amountsof other elements modify the piezoelectric properties of the BaTiO₃materials. Doping of BaTiO₃ materials refers to the inclusion ofsubstoichiometric amounts of other elements.

Examples of suitable single crystal barium titanate materials furtherinclude {(Bi1/2,Na1/2)1-xAlx}TiO3 (A1=Ba, Ca, Sr),{(Bi1/2,Na1/2)1-x(Bi1/2, A21/2)xTiO3 (A1=Ba, Ca, Sr, A2=Li, K, Rb)(Single crystal), (Sr,Ba)3TaGa3Si2O14, La3-xSrxTayGa6-y-zSizO14,(Ba,Ca)TiO₃, LiNbO₃, LiTaO₃, (K3Li2)1-xNaxNb5O15, La3Ga5SiO14,MgBa(CO3)2, NdCa4O(BO3)3 (M1=rare earth elements, M2=alkaline earthmetals), LaTiO2N.

In some implementations, the ejector plate 5502 may be formed of asuitable material where the suitable material is selected based on outof plane displacement, direction 5514. The ejector plate 5502displacement Z (e.g. movement in the direction 5514), depends on thediameter of the ejector plate 5502 and the thickness of the ejectorplate 5502. The suitable material may also be selected in view of theYoung's Modulus and Poisson's Ratio of the ejector plate 5502. TheYoung's Modulus and Poison's Ratio are intrinsic properties of thematerial and conforming materials can be selected to determine a desireddisplacement. For a suitable material for the ejector plate 5502,displacement Z may be increased by decreasing the thickness of theejector plate 5502.

Suitable materials for ejector plate 5502, having a displacement indirection 5514 can be coupled to the frequency of the piezoelectricactuator 5504 so that the resonant frequency of the ejector plate 5502is matched. By coupling the displacement of the ejector plate 5502 withthe piezoelectric actuator 5504 in a resonance system, the ejection ofliquid through the holes of the generator plate 5532 can be accomplishedwith piezoelectric actuator that are not limited by D₃₃ values.

Referring to FIG. 55C, the manner and location of attachment of thepiezoelectric actuator 5504 to the ejector plate 5502 may affect theoperation of the ejector assembly 5500 and the creation of the dropletstream.

As discussed above, the ejector plate 5502, whether as a simple ejectorplate 5502 or as a hybrid ejector plate 5502 coupled to a generatorplate 5502, may possess a large number of eigenmodes which define, foreach eigenmode, the shape the structure will take when said mode isexcited. As provided above, using for example FEM techniques, theeigenmodes of an ejector plate 5502 and optionally coupled generatorplate 5532 may be calculated and the desired amplitude and velocity ofthe eigenmodes determined.

In one embodiment, the piezoelectric actuator 5504 is edge-mounted onthe ejector plate 5502 where the distance 5554 is zero. An edge mountdesign is a special case which has near zero inherent resistance tomodes it is designed to excite. When a circular piezoelectric actuator5504 is bonded to the edge of a circular ejector plate 5502 (e.g., thedistance 5554 is at or near zero) the ejector plate 5502 is stiffenedconsiderably where a stiff piezoelectric actuator 5504 is placed, butthe portion of the ejector plate 5502 on the inside of the piezoelectricactuator 5504 inner diameter 5557 is left to move freely, restrictedonly by its own limits of elasticity rather than the piezoelectricactuator 5504. Similarly, hybrid ejector plates 5502 having a coupledgenerator plate 5532 would also be left to move freely, restricted onlyby the combined limits of elasticity rather than the piezoelectricactuator 5504. If the edges of the piezoelectric actuator 5504 arepinned or clamped, the ejector plate 5502 behaves virtually as though itwas the diameter of inner diameter 5557 of the piezoelectric actuator5504 with ideal (edge driven) radial and longitudinal excitation. Othermodes relevant to the entire size of the ejector plate 5502 aresuppressed due to the stiffness of the piezoelectric actuator 5504. Incertain embodiments, the stiffness of the piezoelectric actuator 5504may be modulated by increasing or decreasing the thickness of apiezoelectric actuator 5504. Embodiments illustrating the modulation ofpiezoelectric actuator 5504 are presented in Example 5 below.

In other embodiments according to the present disclosure, the mountingconfiguration of the piezoelectric actuator 5504 to the ejector plate5502 effects the displacement and velocity of the ejector plate 5502 andthe generator plate 5532. In general, the amplitude of displacement andthe velocity of the ejector plate 5502 in a given mode is a balancebetween the force, largely determined by the movement per unit voltage(D₃₃) of the piezoelectric material, and the damping/resistance that apiezoelectric presents to the ejector plate 5502 movement. Increasingstiffness of the piezoelectric material increases the damping andresistance. For embodiments of the present disclosure havingpiezoelectric materials having a large D₃₃, for example materials likePZT, the damping/resistance of the piezoelectric material plays a lesssignificant role in the amplitude of displacement. In other embodimentswith a lower D₃₃, for example BaTiO₃, the performance of a dropletejector system may be significantly decreased by the damping/resistance.The performance of an ejector assembly 5500 reduces in direct proportionto the D₃₃ of the material used to prepare a piezoelectric activator5504.

The properties of an edge mounted embodiment of a piezoelectric actuator5504/ejector plate 5502 can be used to bypass the effects of lowermaterial movement. Specifically, when the ejector plate 5502 is excitedin a mechanical mode where only its own resistance limits its movementdue to a given force per unit area applied by the piezoelectric actuator5504, the piezoelectric D₃₃ can be scaled down with no impact onperformance for the same electrical input until a minimum force per unitarea value is reached. This property is illustrated in FIG. 8, where ifthe force per unit area is above a certain threshold, the increase inejector plate 5502 movement is very small. Below this threshold, theejector plate 5502 movement decreases linearly with force per unit area.

For ejector plates 5502 of the present disclosure, low order modes aregenerally excited at the lowest frequencies on a structure where thewavelength of the standing wave is an integer multiple of a halfwavelength. The frequency and wavelength of this mode is determined bythe material properties of the ejector plates 5502 and its radialdimension. As the eigenmode shape always possesses a node at the edgesof the ejector plates 5502 for these modes and a maximum at the centerof the membrane, only two piezoelectric locations are relevant forexciting these modes in a fluid ejection system.

In an embodiment according to the present disclosure, a piezoelectricactuator 5504 can be placed in the center of the ejector plate 5502 inorder to excite maximum movement. However, because there must be an areadirectly in the center of the ejector plate 5502 for fluid ejection totake place, this mounting position is not optimum for this application.Performance must be sacrificed to allow fluid ejection.

A piezoelectric actuator 5504 can likewise be placed at the edge of theejector plate 5502 to excite maximum movement in the center of theejector plate 5502 at low frequencies. In this configuration, minimumresistance to the natural movement of the mode occurs, allowing largedisplacements at low frequencies and enhanced mass depositions in thesemodes. Generally, these modes are favorable for continuous fluidejection due to their nearly constant shape and velocity distributionover the ejection area. Furthermore, loading the center of the ejectorplate 5502 with a mass, such as in a hybrid ejector plate 5502 having acoupled generator plate 5532, enhances low order mode displacement dueto the inertia of the center mass (e.g. generator plate 5532).

In some embodiments, the edge-mounted piezoelectric actuator 5504oscillates the ejector plate 5502 coupled to the generator plate 5532 atthe resonant frequency of the ejector plate coupled to said generatorplate. In one embodiment, matching the resonant frequency decreases thedisplacement requirement of the piezoelectric material. In oneembodiment, the resonant frequency matching provides for the generationof a directed stream of droplets using a piezoelectric material having aD₃₃ of less than 200. In another embodiment, the resonant frequencymatching provides for the generation of a directed stream of dropletsusing a piezoelectric material having a D₃₃ of less than 150 or lessthan 125. In yet another embodiment, the resonant frequency matchingprovides for the generation of a directed stream of droplets using apiezoelectric material having a D₃₃ of less than 100 or less than 75.

In another embodiment, the piezoelectric actuator 5504 is slightly lessthan edge mounted (e.g., inside mounted) on the ejector plate 5502 wherethe distance 5554 is greater than zero. In one embodiment, the distance5554 may be 0.05 mm. In another embodiment, the distance 5554 may be0.01 mm. In yet another embodiment, the distance 5554 may be 0.25 mm. Inyet another embodiment, the distance 5554 may be 0.5 mm. In furtherembodiments, the distance 5554 may be 0.75 mm, or 1.0 mm, or may begreater than 1.0 mm.

In other embodiments according to the present disclosure, thepiezoelectric actuator 5504 is inside mounted on the ejector plate 5502where the distance 5554 is greater than zero and the outer diameter ofpiezoelectric actuator 5504 is smaller than ejector plate 5502. In anembodiment, the piezoelectric actuator 5504 is inside mounted on theejector plate 5502 and is 1% smaller than the diameter of ejector plate5502. In an embodiment, the piezoelectric actuator 5504 is insidemounted on the ejector plate 5502 and is 1.5% smaller than the diameterof ejector plate 5502. In an embodiment, the piezoelectric actuator 5504is inside mounted on the ejector plate 5502 and is 2% smaller than thediameter of ejector plate 5502. In an embodiment, the piezoelectricactuator 5504 is inside mounted on the ejector plate 5502 and is 3%smaller than the diameter of ejector plate 5502. In an embodiment, thepiezoelectric actuator 5504 is inside mounted on the ejector plate 5502and is 4% smaller than the diameter of ejector plate 5502. In anembodiment, the piezoelectric actuator 5504 is inside mounted on theejector plate 5502 and is 5% smaller than the diameter of ejector plate5502. In an embodiment, the piezoelectric actuator 5504 is insidemounted on the ejector plate 5502 and is 7.5% smaller than the diameterof ejector plate 5502.

In some embodiments according to the present disclosure, thepiezoelectric actuator 5504 is inside mounted on the ejector plate 5502where the distance 5554 is greater than zero and the inner diameter ofthe annular piezo actuator is selected so that the low frequency edgemode of the ejector plate 5502 is damped or eliminated.

In certain embodiments of the disclosure, the ejector mechanism may beconfigured so as to facilitate actuation of the ejector plate 5502, andthereby the generator plate 5532, by the piezoelectric actuator. Asdescribed above, the generator plate 5532 may be configured to optimizeejection of a fluid of interest. For example, the aspect ratio of theopenings of the generator plate may be selected based, in part, on fluidproperties, such that the general thickness of the generator plate 5532ranges from about 50 μm to about 200 μm, as described above. Withoutbeing limited by theory, in certain implementations, direct actuation ofa relatively thick generator plate, though possible, may be lessoptimal. In some implementations, the generator plate comprises a highmodulus polymeric generator plate.

As such, in certain implementations, actuation of the ejector mechanismmay be optimized using configurations including a generator platecoupled to an ejector plate, as described herein. In addition, reducingthe surface area of the generator plate 5532 (i.e., the central regionhaving one or more openings) likewise reduces manufacturing costs,reduces potential manufacturing defects, and increases manufacturingefficiencies and output. In certain embodiments, the ejector plate maybe sized and shaped in a manner to facilitate actuation of the ejectormechanism (i.e., actuation of the ejector plate and thereby thegenerator plate). By way of example, configurations of the ejector platemay effectuate actuation of the ejector mechanism through selection ofproperties (e.g., size, shape, material, etc.) that facilitate flex ofthe ejector plate, and thereby vibration of the generator plate. Forinstance, the ejector plate 5532 may have a thickness generally rangingfrom about 10 μm to about 400 μm, from about 20 μm to about 100 μm, fromabout 20 μm to about 50 μm, or from about 30 μm to about 50 μm, etc.Again, without being limited by theory, in certain implementations,direct actuation of a relatively thinner ejector plate 5502 (compared tothe generator plate 5532), may be more optimal. In some implementations,the generator plate 5532 comprises a high modulus polymeric generatorplate.

In accordance with certain implementations of the disclosure, theconfiguration of the ejector plate 5502 and the generator plate 5532 maybe selected such that the center region of the generator plate 5532including openings (the “active region” of the generator plate) producesa symmetric oscillation with a normal mode of oscillation. Without beinglimited by theory, in certain implementations, configurations of theejector plate 5502 and generator plate 5532 may be selected such that0.2 normal mode and 0.3 normal mode of oscillation of the active regionof the generator plate is observed. The mode is associated with amaximum amplitude and displacement of the active region, wherein themode is designated as (d,c) where d is the number of nodal diameters andc is the number of nodal circles.

The magnitude and frequency of the ejector plate 5502 vibration can alsobe controlled by controlling the voltage pulses applied to theelectrodes 5506 a, 5506 b, e.g., a voltage differential of 40 or 60 Vmay be applied to the electrodes. As discussed above, the pulses arecreated by voltage differentials that deflect the ejector plate 5502,and thereby generator plate 5532. In some implementations, one of theelectrodes 5506 a or 5506 b is grounded and voltage pulses, e.g.,bipolar pulses, are applied to the other one of the electrodes 5506 a or5506 b e.g., to vibrate the ejector plate 5502. By way of example, inone implementation, the piezoelectric actuator 5504 can have a resonantfrequency of about 5 kHz to about 1 MHz, e.g., about 10 kHz to about 160kHz, e.g., about 50-120 kHz or about 50-140 kHz, or about 108-130 kHz,etc. The applied voltage pulses can have a frequency lower, higher, orthe same as the resonant frequency of the piezoelectric actuator 5504.

In certain implementations, delivery time of the droplets is about 0.1ms to about several seconds. Without wishing to be bound by theory, itis believed that human eyes take about 300 ms to about 400 ms for ablink. Therefore, for implementations where delivery is desired to bewithin the duration of a blink, the delivery time may be about 50 ms toabout 300 ms and more particularly 25 ms to 200 ms. In oneimplementation, the delivery time is 50 ms to 100 ms. In this way, theejected droplets can be effectively delivered and deposited in the eyeduring a blinking cycle of the eye. In some implementations, for exampleover-the-counter saline dispensers, the delivery time can be as long asseveral seconds, e.g., 3-4 seconds, spanning several blink cycles.Alternatively, a single dosage can be administered over several burstsor pulses of droplet ejection. Additionally, and not intending to belimited by theory, pulsing may be used to reduce the peak amplitude ofthe droplet airstream by spreading the impulse out over time. Therefore,the pressure of the ejection on the target may be mitigated.Furthermore, pulsing may also reduce droplet agglomeration and result inless entrained air generation. By way of example, pulses of 25 ms can beadministered with stop times of 25 ms separating the pulses. In oneimplementation, the pulses may be repeated for a total of 150 ms.

As described herein, the ejector device and ejector mechanism of thedisclosure may be configured to eject a fluid of generally low torelatively high viscosity as a stream of droplets. By way of example,fluids suitable for use by the ejector device can have very lowviscosities, e.g., as with water at 1 cP, or less, e.g. 0.3 cP. Thefluid may instead have viscosities in ranges up to 600 cP. Moreparticularly, the fluid may have a viscosity range of about 0.3 to 100cP, 0.3 to 50 cP, 0.3 to 30 cP, 1 cP to 53 cP, etc. In someimplementations, the ejector device may be used to eject a fluid havinga relatively high viscosity as a stream of droplets, e.g., a fluidhaving a viscosity above 1 cP, ranging from about 1 cP to about 600 cP,about 1 cP to about 200 cP, about 1 cP to about 100 cP, about 10 cP toabout 100 cP, etc. In some implementations, solutions or medicationshaving the suitable viscosities and surface tensions can be directlyused in the reservoir without modification. In other implementations,additional materials may be added to adjust the fluid parameter. By wayof example, certain fluids are listed below in Table 15:

TABLE 15 Viscosity measured at 20° C. drugs/fluids dynamic viscosity(cP) kinematic viscosity (cP) density water 1.017 1.019 0.99821Xalatan ™ 1.051 1.043 1.00804 Tropicamide 1.058 1.052 1.00551 Restasis ™18.08 17.98 1.00535

From the above discussion it will be appreciated that differentconfigurations and material will result in different attributes. Inorder to assist in understanding some of these attributes in a fewselect embodiments of the ejector mechanism, experiments were conductedto compare certain embodiments. The experiments described herein shouldnot, of course, be construed as specifically limiting the invention andsuch variations of the invention, now known or later developed, whichwould be within the purview of one skilled in the art are considered tofall within the scope of the invention as described herein andhereinafter claimed.

Example 6: Measurement of Mass Deposition

To measure the mass deposition of an ejector device, the ejector deviseis clamped horizontally to eject material towards to the ground wherethe poled direction Z, as shown in FIG. 56, is toward to the ground(e.g., parallel to gravity). Referring to FIG. 55A, the direction 5514of the ejected droplets 5512 is towards to the ground. A ground wire andpositive wire of the device is connected to an operational amplifier anda current probe and voltage probe are connected to an oscilloscope.

The frequency region that provides for device spraying is initiallydetermined by a frequency sweep through the range of 2 kHz to 500 kHz.The electrical data, including the voltage and current, are recorded andstored. Upon analysis, the spray ranges for mass depositiondetermination are selected. The results are plotted to provide a massejection profile as shown in FIG. 58, for example.

To determine the mass deposition, the frequency and voltage are set, forexample, to a 90V peak to peak (90Vpp) sine wave at a frequency of 50kilohertz (kHz) and the spray from the ejector device is measured 5times on a 24 mm×60 mm No. 1 glass coverslip using a scale with a 1milligram (mg) sensitivity and calibrated with a 1 mg class 1 weightwith traceable certificate. For each measurement, the coverslip isplaced on the scale and the scale is zeroed. The slide is placeunderneath the ejector device and the voltage applied for a definedperiod of time. The slide is returned to the scale and the mass isdetermined and recorded. The coverslip is cleaned, the scale re-zeroedbefore each measurement. A total of 5 measurements are recorded for eachfrequency. The process is repeated with the frequency incrementallychanged based on a predetermined step size (normally 1 kHz).

Example 7: Comparison of PZT to BaTiO₃ Using an Inside Mount EjectorAssemblies

The mass deposition profile of ejector devices having an inside mountedejector assembly are determined using the method described in Experiment6 above to determine the frequency region for device spraying. For boththe PZT and BaTiO₃ piezoelectric materials, the piezoelectric actuator5504 has a 16 mm outer diameter by 8 mm inner diameter, with a height of550 um, mounted to a 20 mm diameter circular ejector plate 5502 50 umthick. In this embodiment, several samples of PZT are compared directlyto BaTiO₃ with PZT ejecting more fluid than BaTiO₃ in approximately theratio of the d33 coefficients of the materials. The only significantlyejecting mode is shown in FIG. 59.

Where the distance 5554 is greater than zero (here, 2 mm), the PZTmaterial provides a broader range of effective frequencies when comparedto BaTiO₃. The maximal mass ejection of the PZT-based ejector is morethan twice the output of the BaTiO₃ ejector. While less efficient, theBaTiO₃ provides maximal mass ejection between 115 and 102 kHz of about 6mg.

7a: Comparison of PZT and BaTiO₃ Using Edge Mounted Ejector Assemblies

Using the method of Experiment 6, mass ejection at different frequenciesis determined using a frequency step size of 1 kHz, beginning at 10 kHzto 500 kHz. The mass deposited in milligrams is plotted versus thefrequency and is shown in FIG. 58 for edge mounted PZT and BaTiO₃piezoelectric actuators having a 20 mm outer diameter by 14 mm innerdiameter of 550 um height piezoelectric on a 20 mm circular 50 um thickejector plate 5502. In this case, several samples of PZT are compareddirectly to BaTiO₃ with PZT and BaTiO₃ ejecting nearly equivalently(adjusted for sample variation) even with vastly different material d33coefficients. As is also apparent from FIG. 58, many modes are excitedwith equivalent performance between materials.

When PZT and BaTiO₃ piezoelectric actuators are edge mounted (that is,the distance 5554 is at or near zero), mass ejection occurs at discreteranges of frequencies corresponding to the resonance coupling betweenthe piezoelectric actuator and the coupled ejector plate 5502 andgenerator plate. While the PZT based device has a D₃₃=330 pC/N and theBaTiO₃ has a D₃₃=160 pC/N, the ejection profiles and efficiencies arevery similar. The centro-symmetric design and edge mounting of thepiezoelectric actuator overcomes the differences in displacementallowing a wide variety of piezoelectric materials to be incorporatedinto the ejection device.

7b: Effect of Decreasing Piezoelectric Actuator 5504 Diameter Relativeto Ejector Plate 5502

As the piezoelectric actuator 5504 is shifted in from the edge of theejector plate 5502 (e.g., the distance 5554 is increased from zero),performance is lost as the ejecting modes are increasingly damped by thepiezoelectric stiffness. In one embodiment the piezoelectric was 20 mmouter diameter by 14 mm inner diameter with an optimized thickness of250 um and an ejector plate diameter of 20 mm. It showed ejectionexceeding all other cases by 20-33%. In another embodiment the outerdiameter of the piezoelectric was altered to 19 mm and the ejector platediameter was changed to 21 mm with an optimized thickness of 200 um. Theejection frequencies remain virtually the same, but opposed to the edgemounted case, ejection is reduced across every mode even thoughpiezoelectric thickness is optimized, (thicknesses from 150 um to 550 umwere lab tested in 25 um increments). In the third embodiment, thepiezoelectric remained at 19 mm outer diameter and 14 mm inner diameterbut the ejector plate was changed to 23 μm. Once again, the thicknesswas optimized to 175 μm to reduce stiffness but all modes are severelysuppressed and performance was degraded over 80%.

Example 8: Comparison of BaTiO₃ Piezoelectric Materials

BaTiO₃ materials having differing properties were distinguished usingScanning Electron Microscopy (SEM). SEM images of two exemplary BaTiO₃materials were obtained and showed a uniform particle size about 2 to 5microns in diameter in the first sample and a fused structure withparticles tens of microns in diameter in the second sample. While bothsamples had similar D₃₃ values, the smaller grain size improvesperformance by lowering the resonance frequencies.

Example 9: Modulation of Eigenmodes

For a circular ejector plate 5502 excited by a piezoelectric actuator5504, increasing the stiffness of the piezoelectric actuator 5504resulted in suppression of high frequency eigenmodes. To test theeffects of increasing the stiffness of the piezoelectric actuator 5504,a first piezoelectric actuator 5504 of 200 um thickness having an outerdiameter of 20 mm and an inner diameter of 14 (20 mm×14 mm) and a secondpiezoelectric actuator 5504 of 400 um thickness (20 mm×14 mm) werebonded to an ejector plate 5502 with an outer diameter of 20 mm (e.g.,edge mounted). The normalized displacement of the two ejector mechanismswere [modeled or measured] at a frequency range from 1 Hz to 3×10⁵ Hz.The greater flexibility of the thinner piezoelectric actuator 5504allows for high frequency complex eigenmodes. In contrast, the thicker,stiffer piezoelectric actuator 5504 limits the eigenmodes to lowfrequency modes limited to the region of the ejector plate 5502 withinthe inner diameter of the piezoelectric actuator 5504 (e.g., inside 14mm).

It will be understood that the ejector assembly described herein may beincorporated into an ejector device and system. Exemplary ejectordevices and systems are illustrated in Ser. No. 13/712,784, filed Dec.12, 2012, entitled “Ejector Mechanisms, Devices, and Methods of Use”,Ser. No. 13/712,857, filed Dec. 12, 2012, entitled “High ModulusPolymeric Ejector Mechanism, Ejector Device, and Methods of Use”, andSer. No. 13/184,484, filed Jul. 15, 2011, entitled “Droplet GeneratorDevice”, the contents of which are herein incorporated by reference intheir entireties.

When fluid is exposed to an air interface, it will evaporate into theair, causing a loss over time of fluid volume. If the fluid has anymineral elements that are left behind, the mixture contents change overtime which results in crystallization at the air-fluid interface.However, if a small air volume around the fluid-air interface is sealed,the evaporation rate and crystallization rate drop to the leak rate ofthe seal, thereby reducing or eliminating evaporation andcrystallization. Contamination is also possible whenever a device isopen to the environment.

In part to address these issues, the present disclosure provides anauto-closing system for use with a droplet ejection device, whichprevents the device from being open to the environment for any longerthat the actual droplet ejection period, which greatly reduces the riskof contamination. In certain embodiments, the auto-closing system isdimensionally compact along the path of fluid ejection, uses a minimumof components, and provides a consistent seal in the presence ofcomponent dimensional variance. The system provides for a closed, sealedposition and an open, active position used for fluid ejection. Thechange between closed and open positions can be configured for manualactuation by a user, or can be configured for powered actuation. Incertain embodiments, the system may provide a manual configuration withlow actuation force. Furthermore, movement between sealed and openpositions can be configured for linear actuation or for rotaryactuation. For instance, certain embodiments provide a linear actuationconfiguration used in conjunction with a user-operated, hingedactivation button.

FIGS. 60-65 show one embodiment of an auto-closure system of thedisclosure. FIG. 60 shows a compact, linearly actuated embodiment of anauto-closing system of the disclosure, and FIG. 61 shows an explodedassembly view of the main components of this embodiment.

As shown in FIGS. 60 and 61, a slide element 6000 with an aperture 6002is retained between the ejection system 6004 to be sealed and aretaining plate 6006. The ejection system is shown schematically withoutreference to internal features. The face of the ejection system has around aperture 6010 surrounded by a round, elastomeric face seal 6012.The face seal resides in a gland or groove 6014 in the face of theejector. In one embodiment, the slide element is squeezed against theface seal by flexures 6020 integral to the slide element. The flexurescould alternatively be located on the retaining plate or could beincorporated as a separate component. In one position of the slideelement (the open position) the slide aperture 6002 is aligned with theejector aperture 6010 for fluid dispensing. In the closed position theslide element aperture 6002 and ejection system aperture 6010 are fullynon-aligned and the ejection system is sealed. A hinged activationbutton 6030 (FIG. 60) pivots about a fulcrum 6031 connected to a housing(not shown). The button 6030 is finger operated by the user and actuatesthe slide element in the downward direction to open the seal. Uponremoval of user finger pressure, a compression spring 6032 returns theslide element 6000 to the closed and sealed position.

FIG. 62 shows a schematic cross-sectional view of the auto-closingsystem and demonstrates the basic sealing principle. An axial force, F,presses the slide element against the elastomeric face seal locatedwithin the gland on the face of the ejection system. The face sealsurface protrudes from the surface of the ejection system byapproximately 20% of the seal cross section. The maximum anticipatedinternal pressure in the ejection system is countered by the axialsqueezing force, F, such that the squeeze force exceeds the internalpressure force given by the product of the internal pressure P and theseal area A. For this embodiment, the axial force was chosen to beapproximately 2× the anticipated internal pressure force. In thepreferred embodiment, the axial squeeze force is provided by compactflexures 6020 as shown in FIGS. 63 and 64. The flexures 6020 provide aconsistent force on the seal that is not sensitive to manufacturingvariance in the dimensions of the components. Having the flexuresintegral to the slide element provides a minimum stack-up height fromthe ejection system to the aperture of the retaining plate, allowing theface of the ejection system to be closer to the final delivery point. Tominimize actuation force the face seal 6012 is formed from apre-lubricated silicone. To prevent abrasion, the slide element 6000 isalways in contact with the seal. No edge of the slide element 6000travels off and back onto the seal 6012; only the slide aperture edgestraverse the face seal. To further prevent abrasion and reduce actuationforce, the slide aperture edge 6040 is rounded and the top edges of theface seal are rounded. To keep the slide element parallel to the faceseal, small glide nubs 6042 are provide on the slide element as shown inFIGS. 63 and 64.

The slide element in the preferred embodiment is injection molded froman anti-microbial thermoplastic. However, the disclosure is not solimited, and any suitable material may be used. As discussed, flexures6020 integral to the slide 6000 provide the pre-load force on the faceseal. Flexure geometry is chosen to provide the desired axial forcewithout over-stressing the thermoplastic. In particular, the maximumstress in the flexure when fully deflected is chosen to be below thelong-term creep limit of the chosen thermoplastic. This ensures that thedesired face seal pre-load is achieved long-term, after the device hasbeen assembled, without stress relaxation in the flexures. Forcompactness, the compression spring 6032 for auto-closing the device islocated in a slot 6044 within the bounds of the slide element 6000. Asmentioned above, two glide nubs 6042 are located on the of the slideelement 6000 to keep the slide element 6000 parallel to the face seal,as the exposed face seal surface protrudes above the guide surface onthe ejection system that constrains the back side of the slide element6000.

As described above, the axial force on the face seal is chosen to exceedthe anticipated internal pressure force by some margin of safety. In theevent the axial force required exceeds the force that can be provided bysmall plastic flexures, an alternative approach is to use a separatespring component, which could be formed from steel. Long term creepissues are not present with a steel leaf spring and the exerted forcecan be increased to provide significant advantages, but with an increasein the cost and space required due to the separate part. One approach toaddress this problem is to use the compression spring 6032 for asecondary purpose as well. The primary purpose of the compression springwould be to provide the auto-closing feature of the device. When userfinger pressure is removed from the activation button, the compressionspring returns the device to the closed and sealed position, passively,without user interaction. To maintain a fully closed device, thegeometry of the device is set such that the compression spring is in apre-loaded state when the slide element is in its fully closed position.This pre-load can be used for the secondary purpose of increasing theaxial force on the face seal, a feature employed in the presentembodiment.

As shown in FIG. 66, in the closed position the activation button 6030interacts with the slide element on an angled, inclined surface 6050.This angle results in a horizontal outward force component acting on thetop of the slide element 6000. A small fulcrum feature (not shown) isintegrated into the top of the retaining plate. The fulcrum is a smallraised portion interacting with the front face of the slide element. Inthe presence of the horizontal force vector, the slide element 6000pivots about the fulcrum causing the lower part of the slide element6000 to pivot toward the face seal to thereby increase the axial forceon the face seal. This increases the seal integrity without the additionof added parts or increased space requirement. Furthermore, the axialforce on the face seal is no longer solely dependent on the flexures,allowing a wider choice of thermoplastics with lower modulus (stiffness)values.

FIGS. 65-68 show a complete schematic representation of one embodimentin both closed (left) (FIGS. 65 and 66) and open (right) (FIGS. 67 and68) positions, with implementation of all features described above. Incertain embodiments, the auto-closing system includes umbrella valves orother suitable pressure relief means utilized in connection with theretention plate (also referred to herein as a compression plate) inorder to address vapor pressure build-up. By way of non-limitingexample, alternative pressure relief systems may include: duckbillvalves; umbrella/duckbill 2-way valves; other suitable pressure releasevalves; pinhole valve in a silicone sheet; slit valve in silicone sheet;single pinhole/vent hole in a rigid material (e.g., 50 micron diameterhole in 50 micron thick stainless steel); an array of vent holes; or anyother suitable pressure relief means that can restore pressureequilibrium quickly enough, while also preventing excess evaporation dueto vapor pressure. Aspects of the umbrella valves or pressure reliefmeans are discussed in further detail herein.

Example 10: Measurement of Crystallization, Evaporation, and Sealing

Crystallization occurs, especially in small holes where the evaporationrate is high, at rates that can be prohibitive to operation of a dropletejector device. If crystallization occurs, it prevents droplet ejectionout of ejector openings by blocking flow.

In accordance with one embodiment, for a generator plate with of 20 umwide holes 50 microns deep with no puncture/capillary plate and openlyexposed to the environment, FIGS. 69 (a)-(c) shows the crystal growthover time for isotonic saline solution. In FIG. 69(a), the ejectoropenings are shown at time zero (fluid has just been inserted into ahard reservoir that is sealed to the ejector mesh (which definesmultiple ejector openings) and shows no crystallization. A stackcompression plate sealingly engages the mesh screen by means of anO-ring and the opposite surface of the mesh screen is attached via anO-ring to a reservoir, the assembly being held together with screws andnuts. At 50 seconds after fluid is inserted, shown in FIG. 69(b),noticeable crystallization begins to form in the ejector nozzles(holes). At 3 minutes, shown in FIG. 69(c), a number of ejector openingsor holes are completely occluded and several ejector nozzles (holes)exhibit crystal growth. The images were acquired by transmission lightmicroscopy, wherein crystals occlude transmitted light through openings.

In order to demonstrate the effect of a fluid loading plate, a systemwas similarly set up, composed of a mesh screen of a generator platewith 20 um wide holes 50 microns deep, but in this case a capillaryplate was added and openly exposed to the environment. FIGS. 70(a)-(c)show the crystal growth over time for isotonic saline solution. In FIG.70(a), the ejector openings are shown at time zero (fluid has just beeninserted into a hard reservoir that is sealed to the ejector mesh viathe following: a stack compression plate, O-ring, mesh screen, O-ring,puncture/capillary plate, O-ring, reservoir held together with screwsand nuts) and no crystallization has occurred. At 5 minutes, shown inFIG. 70(b), still no crystallization has formed. At 6 hours, shown inFIG. 70(c) a number of ejector openings are completely occluded andseveral ejector openings exhibit crystal growth. Although thepuncture/capillary plate cannot reduce the evaporation, it reducescrystallization. The decrease in crystallization rate is obtained bydelivering a constant fluid supply, and preventing mineral deposits notimmersed in fluid.

Evaporation may in certain applications lead to changes in drug strengthand potency, e.g., through loss of water and resulting change inconcentration. Evaporation can also lead to crystallization in ejectoropenings. Table 16 shows evaporation rates from the auto-closure systemof the present disclosure versus evaporation rates with two types ofumbrella valves with different cracking pressures provided in the fluidloading plate. The evaporation rates shown are those exhibited withoutvalve cracking due to pressure fluctuation for isotonic saline using onetype of valve, and for latanoprost and isotonic saline using a differentvalve. Both valves showed very high evaporation rates. In contrast, theauto-closure systems of the present disclosure resulted in a decrease inevaporation rate by a factor of 7-10, depending on the test fluid. Thisalso resulted in an extension of crystallization time by a factor of7-10 in between sprays compared to the puncture/capillary plate andumbrella valves alone.

TABLE 16 Umbrella valve evaporation rates versus perfect face seal usingauto-closure system. Predicted Predicted % Mass Lost Mass Lost fluidlost from Umbrella in 1 day in 30 days 2.0 mL ampoule Fluid Valve (mg)(mg) in 30 days Isotonic 5.3 mm 23.6 707 35% Saline (0.1-0.2 PSIIsotonic vent pressure) 18.0 539 27% Saline Isotonic 20.4 613 31% SalineLatanoprost 5.8 mm 3.5 104 5% Latanoprost (0.2-0.3 PSI 8.6 258 13%Isotonic vent pressure) 11.7 351 18% Saline Latanoprost 7.5 224 11%Isotonic Perfect Seal 2.4 72 4% Saline Latanoprost 2.6 79 4%

In certain aspects of the disclosure, auto-closure systems were utilizedin order to prevent large pressure excursions from forcing fluid out ofthe ejector system. Valves equalize pressure nearly instantly if thepressure exceeds the cracking pressure.

Alternatives to umbrella valves are within the scope of the presentdisclosure. In this regard, any suitable manner for equalizing pressurewhile preventing evaporation may be utilized, e.g., a 50 um and 100 umvent hole solution with a bacteria and fluid resistant membrane filterbonded over the vent hole. This solution also equalizes pressure almostinstantly, 10 psi/0.25 cc per second of air, but also reducesevaporation rates 10-20 times below that of the umbrella valves, asshown in Table 17. Leak rates for pressure equalization (notevaporation) are also shown in Table 17.

TABLE 17 Evaporation and Leak rates for pressure equalization offiltered vent holes Average mass Standard loss per Deviation Number ofCondition day (mg) (mg) samples 50 um hole 1.3 0.3 4 50 um hole & 1.2 ummembrane 0.9 0.2 3 Leak rates from 50 um hole in SS316 steel, 50 umthick (Sample size: N = 10 for each condition) Average CorrectedStandard Leak Rate Leak Rate Deviation Condition (cm{circumflex over( )}3/sec) (cm{circumflex over ( )}3/sec) (cm{circumflex over ( )}3/sec)No 50 um hole (SS316 plate) 0.035 0 0.004 50 um hole 0.431 0.40 0.08 50um hole & 1.0 um membrane 0.428 0.39 0.06 (PTFE on non-woven polyesterLHOP support) 50 um hole & 1.2 um membrane 0.473 0.44 0.13 (acryliccopolymer on non-woven nylon support)

The auto-closure system provides an air and pressure barrier necessaryto prevent evaporation of fluid which could lead to crystallization inthe ejector openings. The purpose of this experiment was to determinethe normal force necessary to produce an auto-closure system sealcapable of sealing at 1.00 PSI.

Using the gravitational force of a plastic sealing element upon thesilicone face sealing ring to determine face seal quality as a functionof normal force. An ABS/Polycarbonate plastic seal element was attachedto the bottom of a beaker so that water could be added for variablemass. The self-lubricating silicone seal was housed inside thecompression plate, with a pressure regulator and pressure gauge attachedto the inside of the compression plate. The variable mass sealingelement was balanced upon the silicone seal, and fluid was added to thebeaker. Pressure data was recorded as a function of face seal normalforce.

As gauge pressure approached 1.00 PSI, the auto-closure system seal masswas increased. Normal forces of 40 grams and larger typically sealed at0.90 PSI or greater. This was identified as an acceptable seal becauseit is significantly higher than the 0.2 PSI umbrella valve ventingpressure.

Another identified condition was that the frictional force of theclosing slider upon the auto-closure system should be less than therestoring force of the auto-closure spring. This condition was fulfilledby choosing a spring with a sufficient spring constant and displacement.

To measure the seal quality provided by the interior auto-closure systemseal over a sequence of multiple sliding actuations. An auto-closuresystem according to the disclosure was attached to an air pressureregulator and pressure gauge. The regulator was set to 1.00 PSI with aperfect seal, and then the perfect seal is removed. The auto-closure isactuated to provide a seal, and the gauge pressure inside the sealincreased until it reached a maximum pressure. This maximum equilibriumpressure is recorded as the seal pressure for that trial.

The maximum equilibrium pressure was recorded for 20 trials, whereafterthe auto-closure system was actuated 100 times. This process wasrepeated 3 more times, resulting in 4 data sets of 20 trials, with 100actuations between each data set. This was designed to test theauto-closure system repeatability over a total of 380 slide actuations.The average seal pressure for each data set is shown in Table 18.

TABLE 18 Auto-closure face seal testing over 380 actuations Data Set #(N = 20 actuations) Average Seal Pressure (PSI) 1 0.940 ± 0.006 2 0.937± 0.007 3 0.934 ± 0.005 4 0.936 ± 0.005 Note: Maximum seal pressure is1.00 PSI because of regulator

A 1.00 PSI seal was identified as an acceptable face seal because itprovides a safety margin above the 0.2 PSI umbrella valve vent. The datafrom this test was consistently within 6-7% of this target sealingpressure over 380 total actuations.

Many implementations of the inventions disclosed in the presentapplication and the above applications that are incorporated byreference have been disclosed. This disclosure contemplates combiningany of the features of one implementation or embodiment with thefeatures of one or more of the other implementations or embodiments. Forexample, any of the ejector mechanisms or reservoirs can be used incombination with any of the disclosed housings or housing features,e.g., covers, supports, rests, lights, seals and gaskets, fillmechanisms, or alignment mechanisms.

Further variations on any of the elements of any of the inventionswithin the scope of ordinary skill are contemplated by this disclosure.Such variations include selection of materials, coatings, or methods ofmanufacturing. Any of the electrical and electronic technology can beused with any of the implementations without limitation. Furthermore,any networking, remote access, subject monitoring, e-health, datastorage, data mining, or internet functionality is applicable to any andall of the implementations and can be practiced therewith. Furthermore,additional diagnostic functions, such as performance of tests ormeasurements of physiological parameters may be incorporated into thefunctionality of any of the implementations. Performance of glaucoma orother ocular tests can be performed by the devices as a part of theirdiagnostic functionality. Other methods of fabrication known in the artand not explicitly listed here can be used to fabricate, test, repair,or maintain the device. Furthermore, the device may include moresophisticated imaging or alignment mechanisms. For example, the deviceor base may be equipped with or coupled to an iris or retina scanner tocreate a unique identification to match a device to the user, and todelineate between eyes. Alternatively, the device or base may be coupledto or include sophisticated imaging devices for any suitable type ofphotography or radiology.

1.-78. (canceled)
 79. A removable ejector assembly and reservoir for an ejector device, comprising: a reservoir containing a fluid; an ejector mechanism having a generator plate and a piezoelectric actuator, the generator plate including a plurality of openings formed through a thickness, the piezoelectric actuator being operable to oscillate the generator plate at a frequency and generate a directed stream of droplets when the ejector mechanism, the ejector mechanism also having a rear surface; and a fluid retention area at the rear surface of the ejector mechanism, the fluid retention area receiving fluid from the reservoir for ejection by the ejector mechanism.
 80. The removable ejector assembly and reservoir for an ejector device of claim 79, further comprising: one or more fluid channels for channeling fluid from the fluid reservoir to the ejector mechanism.
 81. The removable ejector assembly and reservoir for an ejector device of claim 79, further comprising: a fluid loading plate spaced apart from the rear surface of the ejector mechanism; and an ejector mechanism interface which attaches the fluid loading plate to the ejector mechanism.
 82. The removable ejector assembly and reservoir for an ejector device of claim 81, further comprising: a fluid reservoir interface which attaches the fluid loading plate to the reservoir.
 83. The removable ejector assembly and reservoir for an ejector device of claim 79, wherein: the ejector mechanism has an ejector plate coupled to the generator plate and the piezoelectric actuator.
 84. The removable ejector assembly and reservoir for an ejector device of claim 79, wherein: the ejector mechanism and reservoir are configured to be removably mounted to a housing of an ejector device having electronics and a power source for controlling ejection of the fluid from the ejector mechanism.
 85. The removable ejector assembly and reservoir for an ejector device of claim 79, further comprising: at least one needle for transferring fluid from the reservoir to the ejector mechanism; a first mating portion including the at least one needle and being coupled to the ejector mechanism, the first mating portion which forming a receptacle a second mating portion attached to the reservoir and configured to be coupled to the receptacle of the first mating portion, the second mating portion including a puncturable seal.
 86. The removable ejector assembly and reservoir for an ejector device of claim 85, wherein: the first mating portion has a wall that surrounds the at least one needle and defines the receptacle that receives the second mating portion.
 87. The removable ejector assembly and reservoir for an ejector device of claim 85, wherein: the seal is made of a self-sealing material.
 88. The removable ejector assembly and reservoir for an ejector device of claim 85, further comprising: a fitment connected to the reservoir, the fitment defining a secondary reservoir fluidly coupled to the fluid in the reservoir, the fitment also having the second mating portion and the seal.
 89. The removable ejector assembly and reservoir for an ejector device of claim 85, wherein: the first mating portion is snap-fit to the second mating portion.
 90. The removable ejector assembly and reservoir for an ejector device of claim 85, wherein: the at least one needle is movable relative to the seal to move the at least one needle through the seal to fluidly couple the reservoir to the fluid retention area through the at least one needle. 